Acta Obstet Gynecol Scand 1999; 78: 443–446 Copyright C Acta Obstet Gynecol Scand 1999

Printed in Denmark – all rights reservedActa Obstetricia et

Gynecologica ScandinavicaISSN 0001-6349

ORIGINAL ARTICLE

Mitomycin chemotherapeutic pleurodesis topalliate malignant pleural effusions secondaryto gynecological cancerDANNY CHENG 1, YIK-MING CHAN1, TONG-YOW NG1, ANNIE N. Y. CHEUNG2, HEXTAN Y. S. NGAN1

AND LING-CHUI WONG1

From the Departments of 1Obstetrics & Gynaecology and 2Pathology, The University of Hong Kong, Queen Mary Hospital,Pokfulam, Hongkong, Peoples’ Republic of China

Acta Obstet Gynecol Scand 1999; 78: 443–446. C Acta Obstet Gynecol Scand 1999

Background. To assess the efficacy of mitomycin pleurodesis in women with end stage malig-nant effusion.Methods. Retrospective analysis.Results. Of the 13 patients treated six had ovarian, six had endometrial and one had cervicaladenocarcinoma. The median time of onset of effusion from diagnosis of primary diseasewas 12 months (range 1–75). Ten patients were evaluable for response. The median age of thepatients was 59 years (range 42 to 74). Ten (77%) of them had repeated thoracocentesis priorto mitomycin pleurodesis. The median duration and volume of drainage was 4 days (range2–11) and 3.1 liters (range 1.2–10.2) respectively. One of two patients developed a pneumo-thorax and required the insertion of an additional chest drain. Overall, seven patients (70%)responded – one completely (CR) and six partially (PR), while three did not respond. Fourof five patients with ovarian cancer had a partial response, two of four patients with endomet-rial cancer (one CR and one PR) responded. The only patient with cervical cancer had apartial response. Nine patients (69%) had enough symptomatic improvement to be dischargedhome. The drug cost of bleomycin 60 units (US$191), another commonly used agent, wasmore than twice as expensive as mitomycin 30 mg (US$84).Conclusions. Mitomycin pleurodesis can palliate 70% of patients for at least 1 month. It offerscheap and effective palliation. There is a suggestion that patients’ quality of life is improved.

Key words: gynecological malignancy; mitomycin; palliation; pleurodesis

Submitted 20 October, 1998Accepted 22 November, 1998

Symptomatic malignant pleural effusion is a debil-itating condition, commonly afflicting cancer suf-ferers. One aim of treatment is to improve qualityof life as survival can be limited, depending on theprimary disease (1). Clinical practice of chemicalpleurodesis in gynecological patients has largelybeen extrapolated from medical oncological ex-perience. Sclerosants like tetracycline, talc and ble-omycin have been widely used. Large series re-porting their efficacy, however, contain only 18

Abbreviations:CR: complete response; PR: partial response.

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(7%) of 262 patients with a primary gynecologicalcancer (2–4).

Goff et al. (5) successfully used bleomycin intra-pleurally to treat malignant effusions from gyne-cological cancer. There is scant data on survivalafter onset of pleural effusion, especially in the set-ting of tumor recurrence, in gynecological cancer.Clinical impression would indicate that it is brief.Therefore, any subsequent treatment should bepalliative in nature directed towards symptom re-lief. Major surgical procedures associated withhigh morbidity and prolonged hospitalization arecontraindicated. The experience of mitomycin ple-

444 D. Cheng et al.

urodesis in gynecological malignant pleural ef-fusions and on subsequent patient survival is re-ported here.

Material and methods

Between January 1983 and May 1998, intra-pleuralmitomycin was used to treat 13 patients with cyto-logically proven symptomatic effusions of gyne-cological origin. No patients had an antecedentextra-genital cancer and all had end stage disease.None had received chemotherapy within 30 daysbefore or after pleurodesis. All patients had nor-mal leucocytes and platelet counts prior to treat-ment.

An intercostal chest drain was inserted and con-nected to an underwater seal system for free drain-age. The drain was clamped when the daily outputof pleural fluid was less than 250 ml. Mitomycinof a dose between 10 to 30 mg, dissolved in 50 to150 mls of sterile water or normal saline was in-stilled into the pleural space. The patient was repo-sitioned every 15 to 30 minutes to ensure even dis-tribution of the drug. The chest drain was removedthe following day after a chest radiograph showedno pneumothorax. Otherwise, negative pressuresuction was applied. Bilateral effusions weredrained simultaneously but pleurodesis was per-formed sequentially.

Response was assessed 30 days after the pro-cedure, it was complete (CR) when there was norecurrence of effusion on chest radiographs. Par-tial response (PR) occurred when there was recur-rence of the effusion but requiring no further treat-ment and failure when re-treatment was necessary(6). Improvement of quality of life was crudely de-fined when the patient was well enough to be dis-charged home but not to a hospice. Due to theretrospective nature of this study, data on the dur-ation of relief of pleural effusion and formal as-sessment of quality of life are unavailable. All pa-tients had died at the time of analysis and survivalis measured from the time of cytological confir-mation of malignant effusion.

Results

All 13 patients had adenocarcinoma (six ovarian,six endometrial, one cervical). All were treated topalliate end stage disease. The median interval be-tween onset of effusion from diagnosis of primarydisease was 12 months (range 1–75) – 9 months forovarian, 15 months for endometrial cancer. Threepatients (one ovarian and two endometrial) diedwithin 30 days of palliation leaving ten patientsevaluable for response. The median age of the pa-tients was 59 years (range 42 to 74).

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Right-sided effusions were more common thanleft (eight vs. two patients) while three had bilateraleffusions. All had thoracocentesis and ten (77%)of them had the procedure repeatedly prior to ple-urodesis. The median duration and volume ofdrainage was 4 days (range 2–11) and 3.1 liters(range 1.2–10.2) respectively. Eight patients re-ceived 30 mg of mitomycin, three patients had 20mg and two patients had 10 mg.

Two of the 13 treated patients developed apneumothorax but only one (8%) required ad-ditional chest tube drainage. Complete lung re-in-flation occurred in all patients with no case of‘trapped lung’. No patient developed a fever (ofmore than 38æC), bone marrow suppression (leuco-cyte less than 3¿109/liter, platelet count less than100¿109/liter) or pleuritic chest pain requiring an-algesics after treatment.

Nine patients (69%) had enough symptomaticimprovement to be discharged, including one pa-tient who died before evaluation on day 30. Over-all, seven patients (70%) responded – one CR andsix PR, while three did not respond. Four re-sponders (one CR, three PR) received 30 mg, tworeceived 20 mg and one received 10 mg of mitomy-cin. All three non-responders had 30 mg of mito-mycin intrapleurally. Four of five patients withovarian cancer had a PR, two of four patients withendometrial cancer (one CR and one PR) re-sponded. The only patient with cervical cancer hada PR. Due to small numbers, these differences werenot statistically significant.

All patients were dead at the time of analysis.The median survival of the 13 patients was only2.6 months (range 0.3–4.0). Patients with ovariancancer had a median survival of 1.5 months (range0.7–3.8) and endometrial cancer of 2.5 months(0.3–4.0).

Discussion

Advanced ovarian cancer is the leading gynecolog-ical cause of malignant pleural effusion (7). Pleuralmetastases were found in 48% of women who diedfrom ovarian cancer (8). Pleural infiltration leadsto an increase in capillary permeability and exu-date production. These, in addition to tumorblockage of the lymphatic drainage, all contributeto effusion formation. In some women, diseaseprogression or recurrence after conventional ther-apy can manifest as pleural effusion. Shortness ofbreath and decreased exercise tolerance can mark-edly reduce one’s quality of life and self-esteem bylimiting the capacity to perform daily activitiesand self care. Palliation is indicated in patientswith end stage disease and those not responding tosystemic chemotherapy.

Mitomycin pleurodesis 445

Disease control, including malignant pleural ef-fusion, and survival of patients in whom activetreatment is still available would depend on intrin-sic tumor sensitivity to subsequent systemicchemotherapy. Therefore, patients who receivedsystemic chemotherapy within 30 days of pleuro-desis should be excluded from response analysisbecause it was impossible to separate the effect ofmitomycin versus chemotherapy. It would also beerroneous to attribute disappearance of pleural ef-fusion to pleurodesis alone beyond the first fewweeks of treatment. Prolonged effusion controlmust be related to successful systemic disease con-trol. In patients with end stage disease where ‘com-fort care’ is the main aim, it would be inappropri-ate to subject them to repeated radiological exami-nations to assess duration of response. Perhaps itwould also be unrealistic to expect medical pleur-odesis to palliate the symptoms of pleural effusionfor the whole duration of their remaining lives. Ar-bitrarily, response rate was set to be assessed atday 30.

Thoracocentesis and thoracostomy are associ-ated with a failure rate of up to 97% (9). Withrepeated procedures, there are considerable risksof infection and pneumothorax. Medical pleuro-desis has been successfully used to treat malignanteffusion of extra-genital causes. A variety ofchemical, cytotoxics and biologic agents have beenused and tetracycline, talc and bleomycin are the 3most extensively studied. The proposed mechan-ism of action is one of acute inflammatory re-sponse causing fibrosis and obliteration of thepleural space.

Talc has been reported to be the most efficacioussclerosant. Fentiman et al. (10) treated 33 patientswith malignant effusions from breast cancer. Theyfound thoracoscopic talc insufflation (92%) gave asignificantly better control than tetracycline pleur-odesis (48%) at 1 year. After insufflation of aero-solized talc via the thoracoscope, a 96% CR wasreported in 47 patients (11). Morbidity includedtwo cases of trapped lung, six of pulmonary edemaand one of empyema.

Trapped lung is a potentially fatal complicationthat can occur after an induced pneumothoraxduring a thoracoscopic procedure when the in-flammation and fibrosis set in before full re-expan-sion. It is uncommon after medical pleurodesis inthe absence of pneumothorax. With an uninten-tional pneumothorax, instillation of sclerosant canbe deferred until full lung re-expansion to mini-mize the risk of a trapped lung, as in the four pa-tients in this series.

Talc slurry formulations have been used via achest drain. Kennedy et al. (4) reported an 81%success rate at 30 days of 47 evaluable patients.

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Adverse reactions included fever (63%), empyema(5%), cardiac arrhythmias (4%), hypotension (4%)and respiratory failure (4%).

The possibility exists that the six patients whohad partial response to pleurodesis in fact had slowgrowing tumors causing slow re-accumulation ofpleural fluid rather than a true response to mito-mycin. The large volume of fluid (3.1 liters)drained followed by a brief survival (2.6 months)would attest to the aggressiveness and rapidity oftumor growth in the rest of the body. These wouldindicate the responses were real, albeit partial.

The 70% response rate of this report was com-parable to that of a study using bleomycin assclerosant in 22 patients (24 effusions) with ad-vanced gynecological malignancies (5). Bleomycin60 units were injected intrapleurally when the dailysuction drainage was less than 100 mls. A responserate of 71% (CR 42% and PR 29%) at 30 days wasachieved. There were no early deaths after treat-ment. However, in their group of women treatedwith concurrent salvage chemotherapy, it was im-possible to tell whether the effusion resolved be-cause of pleurodesis or systemic effect of chemo-therapy. Fever and pain affected 62% and 9% ofpatients. Two (9%) of 22 patients developed symp-tomatic pneumothoraces requiring treatment.

A fatal case of diffuse alveolar injury has beenassociated with bleomycin pleurodesis (12). Whengiven intravenously, mitomycin can cause marrowsuppression, particularly prolonged thrombocyto-penia and anemia. Inadvertent extravasation intosoft tissue can result in tissue necrosis. However,when administered into the pleural cavity, mitomy-cin is remarkably free from local and consti-tutional side effects in this series. This lack of mar-row suppression is probably related to a slow drugdiffusion from the intra-pleural compartment tothe vascular compartment. Prior to instillation ofmitomycin, the position of the catheter is alwayschecked by radiograph to avoid accidental injec-tion into the chest wall. Luh et al. (13), however,reported fever (11%), pain (7%), dyspnea (7%) andleucopenia (4%) in 47 lung cancer patients treatedby intrapleural mitomycin. This difference couldbe attributable to the retrospective nature of thisseries where not all adverse effects were recorded.Alternatively, this is accounted for by the differentunderlying disease processes.

Operative procedures like pleurectomy (9) andpleuroperitoneal shunting (14) are fraught withmorbidity and are unsuitable for palliation in thisgroup of patients with limited survival (9). Sys-temic chemotherapy is used in a subgroup of pa-tients but symptomatic control of effusion is notimmediate if at all possible. There is also a groupof heavily pre-treated patients where palliation is

446 D. Cheng et al.

the main therapeutic aim. Prolonged hospital stayand treatment time would be against the patient’sbest interest.

It appears that the pleural surfaces must be inapposition before treatment is successful. Responserate is reportedly increased when pleurodesis isperformed after the daily drainage is less than 100mls (6). We proceeded with pleurodesis when thedaily drainage was under 250 mls with the aim ofearlier hospital discharge and had a similar re-sponse rate to that seen in patients treated by Goffand co-workers (5). Villanueva et al. (15) com-pared the efficacy of short term tube thoracostomydrainage with standard tube thoracostomy drain-age before tetracycline sclerotherapy for malignanteffusions in 25 patients. The response rate of 80%was independent of whether tetracycline was in-stilled after the daily output was less than 150 mlsor when the lung was re-expanded by suctiondrainage within 24 hours. This suggests early pleu-rodesis is equally efficacious without compro-mising response and may lead to early discharge.

More than two thirds of our patients were wellenough to be discharged home. One of the aims ofpalliative care is to allow the patient to spend moreof her limited time in the familiar environment ofher own home, given the short median survival ofonly 2.6 months.

Apart from the efficacy of the drug, cost con-tainment is a great concern in current medicaltreatment. In this hospital, it costs more thandouble to treat a patient with bleomycin 60 units(US$191) instead of mitomycin 30 mg (US$84).

Conclusions

Malignant pleural effusion in gynecological malig-nancy can represent a late event with brief patientsurvival regardless of the primary disease. In pa-tients with end stage disease, mitomycin pleuro-desis can palliate 70% of patients for at least 1month which is a substantial time period consider-ing the median survival of 2.6 months. Mitomycinpleurodesis offers cheap and effective palliation.There is a suggestion that patients’ quality of lifeis improved as crudely defined by discharge to theirhomes and it has acceptable morbidity.

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Address for correspondence:

Danny Cheng, F.R.A.C.O.G.Department of Obstetrics and GynaecologyThe University of Hong KongQueen Mary HospitalPokfulam, Hong KongPeoples’ Republic of China