© 2005 Foundation for Promotion of Cancer Research
Management of Malignant Pericardial Effusion with Instillation of Mitomycin C in Non-small Cell Lung Cancer
1 Department of Respiratory Medicine, Maebashi Red Cross Hospital and 2 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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{at}maebashi.jrc.or.jp
Received June 20, 2004; accepted December 11, 2004
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Abstract |
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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
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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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 pericardial 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, we assessed the clinical efficiency and safety in local control of continuous pericardial drainage combined with local administration of mitomycin C through ultrasound-guided catheter insertion.
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PATIENTS AND METHODS |
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PATIENTS
Twenty-one patients with lung cancer-related malignant pericardial effusion, who developed cardiac tamponade or symptomatic 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, radiotherapy or surgery at least 1 month prior to the treatment and (v) written informed consent for the intrapericadial instillation of mitomycin C.
TREATMENT
An 8-French pigtail drainage catheter with multiple side holes (Aspiration Seldinger Kit/Nippon Sherwood Medical Industries Ltd) was inserted using a subxyphoid approach into the pericardial sac under electrocardiographic guidance. Any pericardial 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 concomitant 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 calculated 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).
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RESULTS |
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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 carcinoma (four patients); (ii) malignant pericardial effusions 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 adenocarcinoma 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 recurrence 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.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Several treatments including pericardiocentesis, intrapericardial instillation, surgical creation of a pericardial window, 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 established. 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 established 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 treatment for malignant pericardial effusion (10).
Lee et al. (8) reported that the instillation of 8 mg of mitomycin 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 established 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 µg/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 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 intrapericardial 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 intrapericardial 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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References |
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