Introduction
Malignant pericarditis is observed in 5.1–7.0% of all cases of acute pericarditis [
1]. Malignant pericardial effusion (MPE) can develop into cardiac tamponade, which is a life-threatening disorder [
2,
3]. Breast cancer is the second most common primary cancer associated with MPE [
4]. Previous studies have demonstrated the efficacy of pericardiocentesis and extended catheter drainage is inadequate to prevent re-accumulation of MPE [
5‐
7]. The intrapericardial instillation of various sclerosants such as tetracycline or doxycycline [
8], tetracycline [
9], cisplatin [
10], thiotepa [
11‐
13], mitomycin C [
14], bleomycin [
15], mitoxantrone [
16,
17], minocycline [
18], aclarubicin [
19], and OK-432 [
20] have been reported to be effective in controlling MPE. However, these studies examined a broad range of malignancies, and did not include a sufficient number of breast cancer patients with MPE to establish the most suitable sclerosants specific to this category. In several kinds of malignancies, including breast cancer, tetracycline, cisplatin, and thiotepa were effective, but caused serious complications [
9‐
13]. The efficacy and safety of intrapericardial carboplatin (CBDCA) have never been evaluated in breast cancer. In this study, we assessed the clinical significance of intrapericardial CBDCA following catheter drainage in patients with breast cancer-related MPE.
Patients and methods
Patients
Patients with breast cancer-related symptomatic MPE were included in the study based on the following criteria: (i) symptoms caused by MPE histologically and/or cytologically defined as a result of breast cancer, (ii) 20 years of age or older, (iii) ECOG performance status (PS) 0–3, and (iv) white blood cells ≥ 2000/mm3, hemoglobin ≥ 8.0 g/dL, Platelets ≥ 50,000/mm3, aspartate aminotransferase (AST)/alanine amino transferase (ALT) < 5 times upper limit of normal (ULN), total bilirubin < 3 times ULN, and creatinine < 3 times ULN. Patients were excluded based on serious comorbidity, pregnancy or lactation, active infections, or coagulation disorders.
Treatment method
A catheter was inserted percutaneously into the pericardial space under echocardiographic guidance. After the effusion was completely drained, 150 mg of CBDCA dissolved in 20 ml saline was instilled into the pericardial space through the drainage catheter. The catheter was then clamped and reopened after 2 h. When the drainage volume reached less than 50 ml/day, the catheter was removed. In cases where the catheter could not be removed within 7 days of treatment, CBDCA was administered a second time.
Statistical analysis
Clinical characteristics, MPE control rate at 1 month after treatment, recurrence, complications, survival, time-to-drainage tube removal, and toxicity were assessed based on medical records. Toxicity was judged according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We used a Kaplan–Meier analysis of time-to-event data to estimate median event times. All analyses were performed using GraphPad Prism 8. The protocol complied with the Declaration of Helsinki. Our institution approved this study and all patients provided written informed consent.
Discussion
Malignant pericardial effusion is a potentially fatal complication of cancer. To our knowledge, this is the first study evaluating the efficacy and safety of intrapericardial administration of CBDCA to manage MPE in the patients with recurrent breast cancer. Moriya et al. [
21] showed that the administration of 300 mg of CBDCA to the pericardial space in patients with non-small cell lung cancer (NSCLC) is effective for the control of MPE, with management achieved in nine out of ten patients. Their methods involved instilling 300 mg CBDCA and 100 mg lidocaine dissolved in 50 ml normal saline through the drainage catheter into the pericardial space, after which the catheter was clamped, then reopened after 40 min. In the present study, 150 mg CBDCA dissolved in 20 ml normal saline was infused via catheter, followed by clamping for 2 h. This dose was selected to suit the small body size of our patients (43.5–69.2 kg body weight). We also selected a longer clamping time due to the previous study’s finding that the high concentration of CBDCA in the pericardial effusion was enough to kill cancer cells 1.5 h after reopening the catheter, and that a low concentration of CBDCA in the plasma resulted in management of MPE with little systemic toxicity. This would help to ensure that intrapericardial CBDCA administration is suitable in patients for whom systemic chemotherapy is not appropriate.
In the present study, six patients received systemic therapy after the control of MPE with few adverse events, and the median survival time from the intrapericardial CBDCA administration until death or study follow-up was 552 days, which is longer than previous studies [
4,
8‐
14,
17,
19] (Table
2). Patients with improved PS due to pericardial sclerosis received progressed systemic chemotherapy, contributing to the long survival time after intrapericardial CBDCA administration until death or study follow-up. Median duration of drainage was 9.5–10.5 days in NSCLC [
21,
22]. Duration of drainage in the present study was comparable to that reported in previous studies.
Table 2
Pericardial sclerosis as management of malignant pericardial effusion in cancer patients, including those with breast cancer
Tetracycline or doxycycline | | 68/93 (73.1%) | Pain (n = 17), catheter plugged (n = 8), fever (n = 7), atrial fibrillation/flutter (n = 6), paroxysmal atrial tachycardia (n = 2), development of rub (n = 2), cardiac arrest before sclerosis (n = 2), infection (n = 1) | All: 98 days (1–1724), breast cancer: 131 days (6–1724) |
Tetracycline | | 50/58 (86.2%) | Pain (n = 9), fever (n = 5), atrial fibrillation/flutter (n = 4), catheter plugged (n = 4), development of pericardial friction rub (n = 2), paroxysmal atrial tachycardia (n = 1) | 133 days (3–1149) |
Cisplatin | | 35/42 (83.3%) | Myocardial ischemia (n = 1) | 2.8 ± 1.3 months |
Thiotepa | | 19/19 (100%) | Atrial fibrillation (n = 2), vasovagal reaction (n = 1) | 330 days (15–1040) |
| 30/33 (90.9%) | None | All: 115 days (22–1108), breast cancer: 272 days (47–1108) |
| 19/23 (82.6%) | Transient grade III thombocytopenia and leukopenia (n = 1), grade I leukopenia (n = 1) | 4.5 months (1–26) |
Mitomycin C | | 14/20 (70%) | Pericardial constriction (n = 1) | 101 days |
Bleomycin | | 14/18 (77.8%) | Mild fever (n = 5), atrial fibrillation (n = 3), retrosternal pain (n = 1), infection (n = 1) | Not reported |
Mitoxantrone | | 15/16 (93.8%) | Loss of appetite (n = 1), leukocytopenia (n = 1) | Not reported |
| 2/5 (40%) | Not reported | 122 days (28–294) |
Minocycline | | 10/14 (71.4%) | Severe chest pain (n = 7), pericardial injury (n = 2), vasovagal reaction (n = 1), transient fever (n = 1) | Not reported |
Aclarubicin | | 5/5 (100%) | None | 26 days (13–354) |
OK-432 | | 3/3 (100%) | High fever, chills, chest pain (n = 3) | Not reported |
Present study | | 8/8 (100%) | Fever (n = 1), nausea (n = 1), hypotension (n = 1), fatigue (n = 1), chest discomfort (n = 1) | 552 days (35–1673) |
Apodaca-Cruz et al. [
5] reported a recurrence rate after pericardiocentesis as high as 33% in patients with MPE, including those with breast cancer. The recurrence rate of percutaneous prolonged catheter drainage in patients with MPE including breast cancer is 12–75% [
6,
7]. However, the safety and efficacy of intrapericardial bleomycin compared with pericardial drainage have only been evaluated in lung cancer patients. In these patients, survival with MPE control (effusion failure-free survival, EFFS) at 2 months was not significantly different in patients with drainage alone versus intrapericardial bleomycin (29% versus 46%, one-sided
P = 0.086 according to Fisher’s exact test) [
23]. The recurrence rate of intrapericardial bleomycin for MPE, including breast cancer, was high (22.2%) and three patients (16.7%) developed severe complications [
15]. In Table
2, we list trials evaluating pericardial sclerosis as management of MPE. Thiotepa, tetracycline, and cisplatin are capable of controlling 82.6–100% of MPE, but are associated with severe complications. Mitomycin C, bleomycin, and minocycline have been shown to have some efficacy. In this study, no patients had re-accumulation of MPE 1 month after pericardial sclerosis, and none experienced severe adverse events related to intrapericardial CBDCA administration. On the basis of this, we suggest that carboplatin is a suitable sclerosant for management of MPE.
There are several limitations to this study. As this was a pilot study, we did not specifically evaluate late cardiac complications, and our small patient population did not permit a randomized study to compare intrapericardial administration of CBDCA versus pericardial drainage alone. However, pericardial effusions complicate 1.9% of disseminated breast cancer [
24]. Because of this low incidence, it would be difficult to achieve a prospective study evaluating pericardial sclerosis in an adequate number of patients with a single malignancy.
In conclusion, we found that intrapericardial instillation of CBDCA after catheter drainage appears to be safe and effective for the management of MPE associated with breast cancer. However, as the number of patients in this study was small, a large-scale phase II study is warranted to compare intrapericardial CBDCA administration with extended catheter drainage alone to manage MPE in breast cancer.
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