Jpn J Clin Oncol 2005;35(2)57–60

doi:10.1093/jjco/hyi019

Original Articles

Management of Malignant Pericardial Effusion with Instillation of

Mitomycin C in Non-small Cell Lung Cancer
Kyoichi Kaira1, Atsushi Takise1, Go Kobayashi1, Mitsuyoshi Utsugi1, Takeo Horie1, Takanori Mori1, Hisao Imai1,
Masahito Inazawa1 and Masatomo Mori2
1
Department of Respiratory Medicine, Maebashi Red Cross Hospital and 2Department of Medicine and Molecular
Science, Gunma University Graduate School of Medicine, Maebashi, Japan
Received June 20, 2004; accepted December 11, 2004

Background: To evaluate the clinical efficacy and safety of mitomycin C in the local control of
malignant pericardial effusion, we carried out a trial of pericardial drainage with local instillation
of mitomycin C in eight patients who suffered from cardiac tamponade or symptomatic large
pericardial effusion caused by advanced non-small cell lung cancer.
Methods: After complete removal of the pericardial effusion by an ultrasound-guided inserted
catheter, 2 mg of mitomycin C was instilled into the pericardial space via the catheter.
Results: The drainage catheter was successfully removed in all patients. 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.
Conclusion: Intrapericardial instillation of 2 mg of mitomycin C was feasible and demonstrated
a promising response against malignant pericardial effusion resulting from non-small cell lung
cancer.

Key words: malignant pericardial effusion – mitomycin C – lung cancer – intrapericardial

instillation – pericardial drainage

INTRODUCTION we assessed the clinical efficiency and safety in local control

Malignant pericardial effusion resulting in cardiac tamponade
is a very serious clinical situation. The immediate control
of such pericardial effusions is mandatory for both survival
and an improvement in the performance status (PS) or the
quality of life of cancer patients. Tetracycline hydrochloride,
bleomycin sulfate, cisplatin, carboplatin and mitomycin C have
been reported to be effective in controlling malignant peri-
cardial effusion (1–8). These reports, however, have dealt with
heterogeneous neoplasms and presented no evidence that the
dose of sclerosing agents was optimized. Thus, no standard
treatment for malignant pericardial effusion has yet been
established. Therefore, updated approaches and methods
including the intrapericardial instillation of cytotoxic agents
need to be investigated in a pilot study. We selected mitomycin
C as a cytotoxic agent with a minimal dose and treated eight
patients with cardiac tamponade or large pericardial effusion
due to advanced-stage non-small cell lung cancer. In this study,
For reprints and all correspondence: Kyoichi Kaira, Maebashi Red Cross
Hospital, Department of Respiratory Medicine, 3-21-36, Asahi-cho,
Maebashi, Gunma 377-0014, Japan. E-mail: k-kaira@maebashi.jrc.or.jp
of continuous pericardial drainage combined with local admin-
istration of mitomycin C through ultrasound-guided catheter
insertion.
PATIENTS AND METHODS
PATIENTS
Twenty-one patients with lung cancer-related malignant peri-
cardial effusion, who developed cardiac tamponade or symp-
tomatic large pericardial effusion, were treated at the Maebashi
Red Cross Hospital, between September 1995 and September
2003. Eight of the 21 patients, having met all of the following
eligibility criteria, were enrolled in the study: (i) histologically
and/or cytologically proven non-small cell lung cancer;
(ii) cytologically confirmed malignant pericardial effusions
causing cardiac tamponade or symptomatic large pericardial
fluid; (iii) age from 20 to 80 years; (iv) no chemotherapy, radio-
therapy or surgery at least 1 month prior to the treatment and
(v) written informed consent for the intrapericadial instillation
of mitomycin C.
# 2005 Foundation for Promotion of Cancer Research
58 Management of pericardial effusion with mitomycin C in NSCLC

TREATMENT carcinoma (four patients); (ii) malignant pericardial effusions

An 8-French pigtail drainage catheter with multiple side holes
(Aspiration Seldinger Kit/Nippon Sherwood Medical Indus-
tries Ltd) was inserted using a subxyphoid approach into the
pericardial sac under electrocardiographic guidance. Any peri-
cardial effusions were allowed to drain naturally under gravity
over a 24 h period. After the effusions were completely drained,
2 mg of mitomycin C, dissolved in 10 ml of saline, was instilled
into the pericardial space via the catheter. The catheter was then
clamped for 6 h after mitomycin C administration. When the
daily volume of the drained effusions reached <30 ml, the
catheter was removed. None of the patients received any con-
comitant systemic chemotherapy or radiation during the study.
RESPONSE AND TOXICITY EVALUATION
The response criteria for malignant effusions of the UK Multi-
Centre Study were used to evaluate the efficacy of this
treatment (9). A complete response (CR) was defined as no
reaccumulation of fluid within the first 30 days according to
clinical examination, chest radiography or echocardiogram.
A partial response (PR) was defined as a minimal fluid
recurrence not requiring aspiration within the initial 30 day
evaluation period. Patients requiring reaspiration within
<30 days were classified as treatment failures. The evaluation
period ended with either recurrence of effusion or the patient’s
death. PS was evaluated according to the criteria of Eastern
Cooperative Oncology Group (ECOG). Survival was calcu-
lated from the date of initial instillation of the cytotoxic
agent to the date of death or last follow-up and estimated by
the Kaplan–Meier method. Toxicity was assessed according to
the National Institutes of Health common toxicity criteria
(NCI-CTC version 2).
RESULTS
The characteristics and treatment outcomes of the eight
patients are summarized in Table 1. Thirteen other patients
were not eligible as (i) the tumor cell type was small cell
were not cytologically confirmed (five patients); (iii) they were
>81 years old (three patients); or (iv) written informed consent
could not be obtained (one patient). The eight patients
consisted of six men and two women with a median age of
53.5 years (range 40–69). The tumor cell type was adenocar-
cinoma in all patients. One patient (case 2) was PS 2, whereas
the remaining seven patients were PS 3 or PS 4. Five patients
(cases 3, 4, 6, 7 and 8) developed cardiac tamponade, of whom
four patients were PS 4. Six patients had undergone systemic
chemotherapy as the initial therapy for primary lung cancer
and four patients had received thoracic radiation therapy. The
total effusion volumes aspirated ranged from 880 to 2827 ml
(median 1350 ml). The drainage catheter was successfully
removed in all patients. The duration of pericardial drainage
ranged from 7 to 14 days (median 10.5 days). Among the eight
patients, seven received one instillation of mitomycin C and
one patient received two instillations before the drainage tubes
were removed. The clinical response to treatment was five
CRs, one PR and two failures [response rate 75%, 95%
confidence interval (CI) 34.9–96.8%]. CR patients were recur-
rence free from the instillation of mitomycin C until death,
ranging from 47 to 354 days (median 123 days). Two patients,
determined to be failures due to short survival time, not
attributed to instillation, also had no accumulation of fluid.
Case 8 required one pericardiocentesis on day 34 because of
reaccumulation. However, the patient is still alive without any
recurrence of effusion. All responders improved in terms of
their general condition and could be discharged from hospital.
The overall median survival time for these eight patients was
80 days (ranging from 16 to 364 days). No patients experienced
any adverse effects including complication of drainage
insertion, infection with indwelling pericardial catheters,
pain after mitomycin C administration, arrhythmia, fever or
myelosuppression.
DISCUSSION
Several treatments including pericardiocentesis, intraperi-
cardial instillation, surgical creation of a pericardial window,

Table 1. Patient characteristics and results of intrapericardial mitomycin C treatment

Case Age/sex PS Prior Amount of Duration of Adverse Discharged Response Survival after
therapy effusion (ml) drainage (days) effects from hospital treatment (days)
1 51/M 3 CT + RT 1140 11 None Yes CR 92
2 45/M 2 CT 1594 10 None Yes CR 364
3 51/F 4 CT + RT 1560 7 None Yes CR 241
4 40/M 4 CT + RT 1870 7 None Yes CR 47
5 56/F 3 CT + RT 1102 13 None No Failure 30
6 69/M 4 CT 880 14 None No Failure 16
7 58/M 3 None 2827 12 None Yes CR 123
8 69/M 4 CT 1125 10 None Yes PR 68*

PS, performance status (Eastern Cooperative Oncology Group); CT, systemic chemotherapy; RT, thoracic radiation.
*Still alive.

radiotherapy, systemic chemotherapy or percutaneous balloon
pericardiotomy have been employed for malignant pericardial
effusion (1,10–12). However, most of the studies on these
measures were carried out with small patient numbers, so
no standard treatment for this condition has yet been estab-
lished. The evaluation of clinical efficacy is also difficult
because the treatment of malignant effusions varies depending
on the patients’ clinical conditions and underlying malignancy.
In particular, the presence of pericardial effusion in patients
with non-small cell lung cancer indicates a grave prognosis,
and surgical approaches to malignant effusion are applicable
only for limited cases. Therefore, treatment with an initial
pericardiocentesis followed by indwelling pericardial catheters
is currently appropriate, since radiation therapy and systemic
chemotherapy are not helpful in controlling the pericardial
effusion secondary to lung cancer. It has still not been estab-
lished whether intrapericardial administration of a sclerosing
or cytotoxic agent is superior to pericardiocentesis followed by
drainage due to the lack of a prospective comparative study.
However, a review paper summarizing previous reports showed
that pericardiocentesis has an overall success rate of 44.4%,
indwelling pericardial catheters of 76.3%, and intrapericardial
administration of all sclerosing or cytotoxic agents of 81.6%,
so intrapericardial instillation is a reasonably effective treat-
ment for malignant pericardial effusion (10).
Lee et al. (8) reported that the instillation of 8 mg of mito-
mycin C, dissolved in 10 ml of saline, in the pericardial space
via the catheter every day or every other day has demonstrated
excellent results, although they did not describe the response to
treatment of lung cancer-related malignant pericardial effusion
and improvement in the general condition of the 20 patients.
Malignant pericardial effusion was managed in 14 of 20
patients (response rate 70%) without acute complications.
However, one patient developed pericardial constriction
secondary to intrapericardial instillation of mitomycin C after
6 months and died suddenly due to ventricular arrhythmias
8 months after the pericardial sclerosing therapy (13). Thus,
the instillation of mitomycin C seems to have efficacy and
short-term safety, but the concern regarding long-term safety
seems to remain.
Mitomycin C is a very potent vesicant drug. Therefore,
the dosage and administration of mitomycin C should be
established more cautiously when high concentrations are
administered to a vital organ. The efficacy and safety of
the mytomycin C instillation of 20 mg/50 ml has been estab-
lished in the treatment of superficial bladder cancer (14) and
also the cancer screening data in the National Cancer Institutes
show that mitomycin C exhibits in vitro cytotoxicity at <1 mg/
ml. Thus, taking into consideration the lack of dose escalation
data for pericardial instillation, there may be a possibility that a
lower dose of the mitomycin C instillation could achieve an
equivalent efficacy with better short- and long-term safety
in malignant pericardial effusion, although, of course, the
opposite possibility of insufficient efficacy remains.
Thus, the dosage of one shot administration of mitomycin C
was set at 2 mg/10 ml in this study by referring to the dosage
Jpn J Clin Oncol 2005;35(2) 59
in the intravesical instillation of mitomycin C for superficial
bladder cancer and considering the side effects in the study of
Lee et al. (8) and the performance status of patients. In this
study, we assessed the feasibility of a mitomycin C intraperi-
cardial administration through insertion of an ultrasound-
guided catheter. The drainage catheter was successfully
removed in all patients; seven patients required only one
instillation of mitomycin C. Also, the general condition of
those six patients who responded markedly improved and they
could be discharged from hospital. Afterwards, all responders
except for one (case 8) remained free of effusion recurrence.
Among the five CR patients, two patients died due to pleuritis
carcinomatosa and pneumonia on days 47 and 92, but remained
free of recurrence of effusion until death.
Tetracycline hydrochloride and cisplatin are toxic, with a
high rate of adverse effects including arrhythmia, chest pain,
nausea or fever, and bleomycin sulfate is also toxic, with a low
rate of adverse effects including arrhythmia or fever (1–6).
No adverse effects were observed including complication of
indwelling pericardial catheters under electrocardiographic
guidance during this study.
Among the other 13 patients who were not eligible for
intrapericardial instillation of mitomycin C, seven patients
responded (response rate 53.8%, 95% CI 25.1–80.8), five
patients could be discharged from hospital and four patients
had reaccumulation of fluid. The number is small and we
have not carried out a randomized study comparing the intra-
pericardial administration of mitomycin C versus pericardial
drainage alone. Therefore, these results are not appropriate
for comparison. However, the response rate, improvement
in general condition and efficacy in preventing effusion
reaccumulation tended to be higher in the patients who were
administrated mitomycin C.
The present study demonstrated that the 2 mg mitomycin C
instillation is feasible and has a promising response against
malignant pericardial effusion with acceptable toxicity and it
could be a feasible treatment for patients of poor performance
status. A further trial is warranted to explore the efficacy and
safety of mytomycin C intrapericardial instillation in malignant
effusion due to advanced-stage non-small cell lung cancer.
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