DOI 10.1378/chest.113.5.1305 1998;113;1305-1311 Chest Goodman, Donna K. Culhane, Robert C. Gilkeson and James Herndon Edward F. Patz, Jr., H. Page McAdams, Jeremy J. Erasmus, Philip C. Small-Bore Catheter Drainage of Bleomycin vs Doxycycline with Effusions : A Prospective Randomized Trial Sclerotherapy for Malignant Pleural http://chestjournal.chestpubs.org/content/113/5/1305 services can be found online on the World Wide Web at: The online version of this article, along with updated information and ISSN:0012-3692 ) http://chestjournal.chestpubs.org/site/misc/reprints.xhtml ( written permission of the copyright holder. this article or PDF may be reproduced or distributed without the prior Dundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright1998by the American College of Chest Physicians, 3300 Physicians. It has been published monthly since 1935. is the official journal of the American College of Chest Chest 1998 by the American College of Chest Physicians by guest on July 24, 2011 chestjournal.chestpubs.org Downloaded from
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DOI 10.1378/chest.113.5.1305 1998;113;1305-1311Chest
Goodman, Donna K. Culhane, Robert C. Gilkeson and James HerndonEdward F. Patz, Jr., H. Page McAdams, Jeremy J. Erasmus, Philip C. Small-Bore Catheter Drainageof Bleomycin vs Doxycycline withEffusions : A Prospective Randomized Trial Sclerotherapy for Malignant Pleural
written permission of the copyright holder.this article or PDF may be reproduced or distributed without the priorDundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright1998by the American College of Chest Physicians, 3300Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
1998 by the American College of Chest Physicians by guest on July 24, 2011chestjournal.chestpubs.orgDownloaded from
Sclerotherapy for Malignant PleuralEffusions*A Prospective Randomized Trial of Bleomycin vs
Doxycycline with Small-Bore Catheter DrainageEdward F. Patz, Jr., MD; H. Page McAdams, MD; Jeremy J. Erasmus, MD;Philip C. Goodman, MD, FCCP; Donna K. Culhane, MD;Robert C. Gilkeson, MD; and James Herndon, PhD
Background: Malignant pleural effusions are a common problem for patients with metastaticdisease. Most patients are treated with tube thoracostomy and sclerotherapy, although thereremains no standard approach. The purpose of this study was to compare the efficacy ofbleomycin with doxycycline sclerotherapy for the treatment of malignant pleural effusions usingsmall-bore catheters.Methods: All patients with a symptomatic malignant pleural effusion referred for chest tubedrainage and sclerotherapy over a 2-year period were considered eligible. Using image guidance,a 14F self-retaining catheter was inserted into the pleural space and connected to continuous wallsuction. When drainage fell below 200 mL/d, patients were randomized to 60 U of bleomycin or
500 mg of doxycycline sclerotherapy. Response at 30 days was determined.Results: One hundred six patients were enrolled in the study. Fifteen men (29%) and 37 women (71%)with a mean age of 57 years received bleomycin sclerotherapy. Twenty-one ofthe 29 patients (72%)alive and evaluable at 30 days had successful sclerotherapy. Twenty-three men (43%) and 31 women(57%) with a mean age of 61 years received doxycycline sclerotherapy. Twenty-three of the 29patients (79%) alive and evaluable at 30 days had successful sclerotherapy. There was no significantdifference in response rates between doxycycline and bleomycin (p=0.760).Conclusions: These data continue to support a role for small-bore chest drainage and sclerotherapy,although there was no significant difference in 30-day response rates between doxycycline and
Abbreviations: CI=confidence interval; CR=~complete response; ENR=died (expired) without reaccumulation;EWR=died (expired) with reaccumulation; LTF.unavailable for (lost to) follow-up; PA=posteroanterior; PD=progressivedisease; PR=partial response
\M alignant pleural effusions are a common cause-*¦*¦*¦ of morbidity in cancer patients with advanceddisease. Most patients present with progressive dys¬pnea, cough, or chest pain that compromises theirquality of life.1-4Treatment options depend on a number of factors
such as cell type, extent of disease, performancestatus, and life expectancy. While some tumors andpleural collections respond to systemic chemother¬apy, many patients require local intervention forsymptomatic relief. Tube thoracostomy with sclero-
*From the Department of Radiology, Duke University MedicalCenter, Durham, NC.Manuscript received Julv 11, 1997; revision accepted October 8,1997.Reprint requests: Edward F. Patz, Jr., Dept of Radiology, Box3808, Duke University Medical Center, Durham, NC, 27710
therapy, repeated thoracenteses, or (less commonly)pleuroperitoneal shunts have been effective means
of palliation. Successful sclerotherapy probably de¬pends on a variety of technical and clinical featuressuch as tube size, sclerosing agent, amount of initialpleural fluid, and tumor burden. Given all of thesevariables, there has been no uniform agreement as tothe most effective treatment protocol for malignantpleural effusions. This prospective randomized trial wasinitiated in an effort to determine sclerotherapy7 re¬
sponse rate differences between doxycycline and bleo¬mycin widi the use of small-bore chest drainage tubes.
Materials and Methods
Over a 2-year period, all patients with a known malignancy anda symptomatic, cytologically proved or strongly suspected malig-
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nant pleural effusion referred to the interventional thoracicradiology service for drainage and sclerotherapy were consideredeligible. Patients who had prior sclerotherapy or a drug allergy toone of the sclerosing agents were excluded. No patient hadsystemic chemotherapy immediately prior to or during the 30-dayinterval following sclerotherapy. All patients signed an informedconsent release approved by our Institutional Review Board.Each patient had predrainage baseline posteroanterior (PA)
and lateral chest radiographs. Using image guidance, includingfluoroscopy, ultrasound, or CT, a 14F self-retaining all-purposedrainage catheter (Medi-tech; Boston Scientific Corp; Water-town, Mass) was placed into the pleural space using sterileSeldinger technique. The drainage catheter was inserted in themidaxillary line, at a level chosen by ultrasound guidance. Up to1 L of fluid was aspirated at the time of the procedure dependingon the patient's symptoms. The catheter was then connected to a
water seal device (Pleur-evac; Deknatel Inc; Fall River, Mass) at20 cm H20 continuous wall suction. Daily tube outputs were
recorded, and when drainage fell below 200 mL in a 24-h period,PA and lateral chest radiograph were obtained to assure that thefluid had been sufficiently evacuated, there were no loculatedcollections, and the lung had fully reexpanded. If there were anysignificant loculated pockets of fluid, patients were given an
intrapleural dose of streptokinase, 250,000 IU in 100 mL ofnormal saline solution.Once all fluid was evacuated, patients were randomized to
treatment with 60 U of bleomycin in 50 mL of normal salinesolution or 500 mg of doxycycline mixed with 10 mL of 1%lidocaine and 50 mL of normal saline solution. The sclerosingagent was introduced into the pleural space through the tube,which was then closed to wall suction for 2 h while the patientschanged position (rotated 90°) every 15 min. The tube was thenreopened to wall suction for an additional 18 to 24 h. If thepostsclerotherapy drainage was >200 mL, patients received a
second dose of the same sclerosing agent. The drainage catheterwas then removed. Complications from the procedure were
recorded.Postsclerotherapy PA and lateral chest radiographs were ob¬
tained immediately after tube removal and compared withanother study obtained 30 to 45 days following the procedure.The radiographic response was determined on PA and lateral
upright chest radiographs by observing the level of fluid meniscusoverlying the costophrenic or vertebrophrenic angles and was
defined as follows: complete response (CR) = no reaccumulationof pleural fluid; partial response (PR)= reaccumulation of fluidabove the postsclerotherapy level but below the original level;progressive disease (PD)=reaccumulation to or above thepredrainage level; died (expired) without reaccumulation(ENR)=patient died before 30-day follow-up without reaccumu¬
lation of fluid; died (expired) with reaccumulation(EWR)=patient died before 30-day follow-up with reaccumula¬tion of fluid on chest radiograph; or unavailable for (lost to)follow-up (LTF)=patient had no further evaluation (eg, referredto hospice care).Comparison of response rates between bleomycin and doxycy¬
cline was performed using Fisher's Exact Test. Three patientsubgroups (responders [CR and PR], failures [PD], and expired/lost [ENR, EWR, and LTF]) were compared with respect to
drainage amount and tube duration using the Kruskal-Wallis test.
Results
One hundred six patients with a mean age of 59years were randomized to bleomycin or doxycyclinesclerotherapy for the treatment of a malignant pleu¬ral effusion.
Bleomycin SclerotherapyFifty-two patients, 15 male (29%) and 37 female
(71%), with a mean age of 57 years received bleo¬mycin sclerotherapy. Twenty patients (38%) hadbreast carcinoma, 8 patients (15%) had lung carci¬noma, and 5 (10%) had ovarian carcinoma. Nineteenpatients (36%) had other types of primary tumors(Table 1).Chest tubes were removed within 5 days in 79% of
patients (mean, 4.6 days; range, 2 to 11 days). Totalpleural fluid drained ranged from 340 to 9,860 mL(mean, 2,725 mL). At 30 days, 29 patients (56%)were alive, 13 patients (25%) had died, and 10patients (19%) were unavailable for follow-up. Ofthe 29 patients who were alive, 12 patients (41%) hada CR, 9 patients (31%) had a PR, and 8 patients(28%) had PD. Of the 13 patients who died before30 days, 11 patients had ENR and 2 patients hadEWR.Two patients had loculated fluid demonstrated by
chest radiographs, and each received a single dose ofstreptokinase. At 30 days, one of these patients had a
PR and the other had PD.One patient had 210 mL of fluid drainage after the
first dose of bleomycin, and thus received a seconddose the following day. At 30 days, this patient had a
PR.Complications from bleomycin sclerotherapy in¬
cluded fever in seven patients (13%), local chest painin six patients (11%), shaking chills in two patients(4%), and mild dyspnea in two patients (4%). Symp¬toms resolved in all cases within 24 h with supportivecare.
Doxycycline SclerotherapyFifty-four patients, 23 men (43%) and 31 women
(57%), with a mean age of 61 years received doxy¬cycline sclerotherapy. Fourteen patients (26%) hadbreast carcinoma, 24 patients (44%) had lung carci¬noma, and 5 (9%) had lymphoma. Eleven patients(20%) had other types of primary tumors (Table 1).Chest tubes were removed within 5 days in 68% of
patients (mean, 4.9 days; range, 2 to 13 days). Totalpleural fluid drained ranged from 250 to 9,193 mL(mean, 2,485 mL). At 30 days, 29 patients (54%)were alive, 9 patients (17%) had died, and 16patients (29%) were unavailable for follow-up. Ofthe 29 patients who were alive, 10 patients (34%) hada CR, 13 patients (45%) had a PR, and 6 patients(21%) had PD. Ofthe nine patients who died before30 days, eight patients had ENR and one patient hadEWR.Four patients had loculated fluid demonstrated by
chest radiographs, and each received a single dose of
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streptokinase. At 30 days, one of these patients had a
CR, two had a PR, and one had PD.One patient had 405 mL of drainage output after
the first dose of doxycycline, and thus received a
second dose the following day. At 30 days, thispatient had a PR.
Complications from doxycycline sclerotherapy in¬cluded local chest pain in 11 patients (20%) andnausea in 1 patient (2%). Symptoms also resolved inall cases within 24 h with supportive care.
Comparison Between Response Rates: Analysis ofall patients enrolled (n=106) revealed a CR-PR
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response rate of 40% (n=21) (90% confidence inter¬val [CI], 29 to 53%) with bleomycin, and a CR-PRresponse rate of 43% (n=23) (90% CT, 31 to 55%)with doxycycline. This was not statistically significant(p= 0.846) (Tables 2 and 3).
Analysis of those patients alive at 30 days with a
follow-up study (n=58) demonstrated a CR-PR re¬
sponse rate of 72% (n=21) (90% CI, 56 to 85%) withbleomycin, and a CR-PR response rate of 79%(n=23) (90% CI, 63 to 91%) with doxycycline. Thisalso was not statistically significant (p= 0.760) (Ta¬bles 2 and 3).
In addition, there was no statistically significantrelationship between tube duration and response or
total amount of fluid drained and response (p^O.152and p=0.897, respectively).
Discussion
In patients >60 years, most exudative pleuraleffusions are caused by metastatic disease, most
commonly from lung, breast, and ovarian carcinoma,and lymphoma.5-7 Approximately 50% of patientswith breast carcinoma, 25% of patients with lungcancer, and 35% of patients with lymphoma willdevelop a malignant effusion during the course oftheir disease.3-8
Malignant pleural effusions are typically exudates,with high protein and lactate dehydrogenase levels.They may also be grossly hemorrhagic or have a
marked predominance of lymphocytes and mono¬
cytes.5'910 In many patients, a presumptive diagnosisis made without cytologic study and treatment isinitiated on the basis of a new exudative effusion inthe setting of a known malignancy and in the absenceof another reasonable etiology (eg, infection).Management of malignant pleural effusions de¬
pends on the underlying malignancy, extent of dis¬ease, potential effectiveness of treatment, and per¬formance status. In patients with lymphoma, smallcell lung cancer, or germ cell neoplasms, pleural
Table 3.Response Rates
PatientPopulation
TreatmentGroup Estimate 90%. CI
All patients
Evaluable patients*
BleomycinDoxycyclineBleomycinDoxycycline
21/52=0.4023/54=0.4321/29=0.7223/29=0.79
0.29, 0.530.31, 0.550.56, 0.850.63, 0.91
*Patient alive at 30 days with a reassessment of the pleural effusion.f Ratio of the number of CRs or PRs documented at 30 days over thenumber of patients in the patient population.
effusions may be controlled initially by systemictherapy alone. In patients with metastatic breast or
non-small cell lung carcinoma, local palliative ther¬apy is often required. Since malignant effusions are
frequently a preterminal event with a 30-day mortal¬ity rate of 29 to 50%,3>8'n treatment is directedtoward symptomatic relief with minimal discomfort,inconvenience, and cost.
Local treatment options include repeated thora-centeses, chest tube drainage with sclerotherapy,pleuroperitoneal shunt, or pleurectomy. Repeatedthoracentesis is usually a temporizing measure forpatients with a short expected survival or for whomresponse to systemic therapy is pending. It can beperformed on an outpatient basis and is inexpensive,but it is uncomfortable and carries the risk ofpneumothorax and pleural infection.2 Inpatientdrainage with large-bore (28 to 36F) tubes con¬
nected to wall suction is effective, with variable30-day success rates reported between 55% and95%.21215 For this reason, large-bore tube thoracos¬tomy with sclerotherapy has become the most com¬
mon palliative treatment for malignant effusions.1618Tube thoracostomy, however, requires hospitaliza¬tion, is expensive, uncomfortable, significantly limitspatient mobility, and has associated complications,including empyema.2'4111319~22
Recent studies have shown that small drainagecatheters (10 to 14F) are as effective as large-bore
Table 2.-Summary ofEffusion Response at 30 DaysResponse Bleomycin Doxycycline
CR at 30 dPR at 30 dRecurrence at 30 dDead at 30 d without documentation of recurrence
Dead at 30 d with documentation of recurrence
LTFNo. of patients
12 (23%)9(17%)8(15%)*
11 (21%)2 (4%)10 (19%)+52
10 (19%)13 (24%)*6(11%)8 (15%)1 (2%)
16 (30%)754
*Includes one patient who was treated with bleomycin on the right side and doxycycline on the left side.fThe primary tumors of these patients were melanoma (one), breast (four), ovary (one), lung (three), and mesothelioma (one).'Lymphoma (two), breast (four), lung (eight), pancreatic (one), and rectal (one).
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chest tubes in the treatment of malignant effu¬sions.19-23-26 Using imaging (fluoroscopy, ultrasound,or CT) guidance, small tubes can be placed intoloculated collections, are well tolerated, and havecomplication rates less than the large-bore tubes.2427Because of their size and mobility, small-bore tubesare also well suited for outpatient therapy.28Numerous sclerosing agents have been used to
treat malignant pleural effusions, although mosteffective sclerosing agents create a chemical pleuritisthat fuse the parietal and visceral pleura, thus pre¬venting fluid reaccumulation. Until recently, tetracy¬cline was the most commonly used sclerosing agentwith response rates ranging from 25 to 100% (mean,72%).29-31 Because the IV form of tetracycline is no
longer available in the United States, doxycycline hasbeen proposed as an alternative. In one study,Kitamura et al32 observed an overall response in 11of 15 patients, but more than one instillation was
required.32 There were no responses after a singleinstillation, two patients responded after two instil¬lations, seven responded after three instillations, andtwo responded after the fourth intrapleural instilla¬tion of the agent. The most common adverse effectof intrapleural doxycycline was chest pain that can besevere.16 In another study, small-bore tubes withdoxycycline sclerotherapy had an 80% 30-day re¬
sponse rate with only minimal complications.24Bleomycin has been studied extensively as a scle¬
rosing agent.15'3338 The recommended dose for in¬
trapleural instillation is 60 U, or 1 U/kg of bodyweight, dissolved in 50 to 100 mL of normal salinesolution. The dose should be reduced to 40 U/m2 inthe elderly. Intrapleural instillation is usually welltolerated but a few patients may report mild fever or
transient nausea. Pleuritic pain and rigors are rarelyreported side effects. This relative lack of systemictoxicity is likely due to limited absorption of bleomy¬cin (approximately 40%) from the pleural cavity.39Because the drug is not myelosuppressive, it can beadministered safely to patients with compromisedimmune function, including those receiving otherchemotherapeutic agents. At 30 days, bleomycin hasbeen reported to be superior to tetracycline.17'40'41Although the incidence of other side effects was
similar for both drugs, pain was reported almosttwice as frequently in patients treated with tetracy¬cline. Because of its efficacy and low incidence ofside effects, bleomycin has been suggested as a
suitable alternative to tetracycline.Talc has proved to be one of the most effective
sclerosing agents for treating malignant pleural effu¬sions. It has not gained universal acceptance becauseof its complications. Talc causes a severe pleuritisresulting in effective pleurodesis, but can worsen
pain and dyspnea in these patients and can result in
respiratory failure.1442 Other complications asso¬
ciated with talc pleurodesis include fever, acute
pneumonitis, granulomatous pneumonitis, andempyema.29'42-47 Talc is instilled either as a slurryvia chest tube or insufflated via thoracoscope. Thelatter method attempts to assure uniform distribu¬tion. The dose of talc used for pleurodesis hasranged from 2 to 10 g (recommended dose, 5 g).The higher doses have been associated with an
increased incidence of adverse effects, especiallyrespiratory failure.14 Randomized studies compar¬ing the efficacy of talc sclerotherapy with othercommonly used agents such as bleomycin andtetracycline have shown higher success rates withtalc pleurodesis.29'3133 However, because of theexpense of hospitalization, surgery, and generalanesthesia, and associated complications, furtherinvestigations are needed to define its role in thetreatment of malignant pleural effusions.Many other chemotherapeutic agents such as
doxorubicin, cisplatin and cytarabine combination,etoposide, fluorouracil, and mitomycin have beenused for sclerotherapy. In addition, radioactive iso¬
topes, Corynebacterium parvum, interferon, and re¬
combinant interleukin-2 have been instilled in thepleural space for treatment of malignant pleuraldisease. Response rates have been variable and lessthan optimal. Side effects are not inconsequential,and thus none of these agents have gained wide¬spread use.4869
Malignant pleural effusions continue to be a com¬
mon problem in patients with metastatic disease.There have been numerous studies addressing theetiology, diagnosis, and treatment, although therestill remains no standardized approach to this disor¬der. Local treatment of malignant pleural effusions is
palliative and should be directed at minimizingdiscomfort, cost, and complications. This study sup¬ports a role for small-bore tubes, which were welltolerated, had satisfactory response rates, and mini¬mal complications. The study found no statisticaldifference between the two agents, and found thattube duration and amount drained were not predic¬tive of 30-day response rates. It also became appar¬ent that for successful sclerotherapy, complete evac¬
uation of the pleural fluid and total lung reexpansionwere essential before introducing the sclerosingagent. Other features, including tube size and dailyflow rates, appear to be of limited value in predictingresponse rates.As we continue our efforts to optimize sclerother¬
apy protocols, we must recognize that this is usuallya temporizing or palliative solution and quality-of-lifeissues should be of ultimate concern.
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DOI 10.1378/chest.113.5.1305 1998;113; 1305-1311Chest
Goodman, Donna K. Culhane, Robert C. Gilkeson and James HerndonEdward F. Patz, Jr., H. Page McAdams, Jeremy J. Erasmus, Philip C.
Catheter DrainageRandomized Trial of Bleomycin vs Doxycycline with Small-Bore Sclerotherapy for Malignant Pleural Effusions : A Prospective
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1998 by the American College of Chest Physicians by guest on July 24, 2011chestjournal.chestpubs.orgDownloaded from
