Treatment of Malignant Khaled Reshad, M.D.; Kenji Shigeki Hitomi, M.D., F.C.C.P.t Inui; Pleural Yoshiki Takeuchi; Yutaka hundred effusion were nant pleurisy mesothelioma; Adenocarcinoma most frequent The modalities consecutive patients with malignant pleural reviewed. The pathologic etiology of maligwas: primary lung cancer in 123 cases; five, and 72 cases secondary to metastatic tumors. of the lung and mammary cancer were the tumors causing malignant pleural effusion. employed in local treatment consisted of thoracocentesis in 62 patients, tube thoracotomy in ifi cases with local instillation of adriamycin, MMC, CQ, 5FU, 0K432 or talc. Surgical procedures including pleuropneumonectomy or reduction surgery of the tumor with decortication were performed in ten patients. Tube drainage with 1.\vo C arcinomatous pleurisy is not uncommon as a manifestation ofcancer, and often results in significant pulmonary and cardiac insufficiency threatening the life ofthe fluid, patient. The also to prevent and sion. Despite in use today, this cocentesis Various methods recurrent fluid, or tube injection been the of effu- such to the decortication, advocated multiple drainage agents, Radiation with been have pleural materials tetracycline. cotomy is to remove reaccumulation including of antineoplastic sclerosing and treatment the the many methods tried in the past and no single method of treatment is entirely satisfactory. prevent ideal with or without radioactive isotopes as talc, quinacrine chest wall, open and to thora- pleurectomy This report with presents a review a series carcinomatous of pleurisy. determine the The effect ofour experience consecutive 200 also results of therapy were and thoracoinitial results were obtained in patients who received reduction surgery with decortication and pleurodesis. Results of cytologic investigation were positive in 157 cases (78.5 percent). The tumor cells disappeared in 79.4 percent of primary cancer pleurisy cases and 8L1 percent of patients with metastases while disappearance or significant decrease in pleural effusion following treatment was obtained in 75.2 and 77.8 percent respectively. The median survival was 11.3 months in primary cases, and 11.7 months in patients with for malignant ofMalignant Diagnosis The film, diagnosis analyzed to its significance in chest computed METHODS Pleurisy of malignant pleurisy tomography, was and provided cytologic by chest examinations x-ray of the pleural fluid obtained by initial thoracocentesis. More invasive diagnostic procedures such as needle biopsy, pleuroscopy or pleural biopsy during open drainage and decortication were performed in patients with several negative cytologic investigations of pleural efflisions. The records Denryoku of consecutive Tenri Hospital Hospital, Shimada City, tChest Diseases Research Japan. Institute, *From Manuscript Reprint Hospital, Hospital, 200 the Department of Chest and patients treated Shimada Municipal Diseases, Kyoto Shimada University, at without pleural effusion more was local effective therapy. than Excellent betweenJanuary, were reviewed in this series. There were 1.23 malignant pleural 1975 and December, due to primary 1983 cancer with 85 years. patients an average patient Seventy-six had patients bilateral effusions 67.8 years were men malignant ofage, and pleural lung from 32 to ranging 47 were effusion; women. 65 had Nine right sided, and 49 had left sided hemithorax. The histologic distribution ofprimary lung cancer causing malignant pleural effusion is listed in Table 1. Malignant pleurisy secondary to metastatic tumors ofwhich and 29 were Their The listed average age pathologic in Table mesothelioma right-sided, was involved 53 years, etiology 52 women 32 left-sided with of metastatic and and 16 bilateral the range malignant 13 to 84 pleurisy is 2. A variety of modalities was employed in local treatment of malignant pleural effusion. They included thoracocentesis or tube intercostal drainage with or without instillation of antineoplastic drugs, sclerosing agents, and surgical procedures such as pleuropatients, (llsble four drainage therapy. included and AND or metastases. partial MATERIAL of drugs with pneumonectomy with prognosis. CLINICAL and instillation centesis years. since patients local pleurisy. described. 1975 Takahashi; 25 men, and thora- have Effusion* times Thoracocentesis patient on was average, resection of the pleurodesis in therapy instillation was local therapy. The drugs primary performed instilled adriamycin as tube site of the tumor in 16 patients in 62 intercostal into the pleural (20 mg), cavity mitomycin materials. These or in combination, injected into the pleural singly agents were local of rejection during of the tube drainage 5FU (500 drugs; OK432(10 talc or tetracycline selected in 20 ml through effusion. without C (10 to 20 mg), dissolved cavity decortication pleural because (10 mg) as antineoplastic immunotherapeutic agent and an sclerosing with six patients with malignant with a systemic chemotherapy and carbazilquinone KE) applied and was performed in 111 cases with an average of 16 days of Ten patients were subjected to surgical procedures which pleuropneumonectomy in four cases, and lobectomy or Palliative were 3). per randomly of saline a chest tube and solution which mg) to 20 as used and was then Kansai Table Hospital Municipal Kyoto, Japan. received November 19; revision accepted February 26. requests: Di Reshad, 1200-5 Noda, Shima Municipal Shimada City, Shizuoka, Japan 427 1-Histology (Primary Adeno car Sqcellcar Large cell car ofCarcinomatous Lung 123 Cases) 71 Small 24 Alvcellcar 7 CHEST Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 Cancer, Pleurisy cell car 6 5 Others I 88 I 3 I SEPTEMBER, 10 1985 393 Table 2-Histology Pleurisy ofCarcinomatous and Mesothelioma M#{233}tastatic Tumors 25 Thyroid Castroint t Utero-ovar t Mal Lymph 22 Sarcomas MalThym 4-Treatment Carcinomatous Effectiveness Pleurisy in (77 Cases) c Mammary Table t Disappearance Tumor cells 3 2 6 Kidney 5 Others t 2 2 5 Mesoth 5 Primary of in Decrease of Survival lime P1 Fluid P1 Fluid (Months) 79.4% 75.2% 11.3 81. 1% 77.8% 11.7 Ca Pleurisy Metastatic Table Palliative 3-Treatment Pleurisy ofCarcinomatous therapy Thoracocenteses Pleurisy 17 Cases local instillation 62 Cases peutic 4. agent (Av 4 times/pt) Tube thoracostomy 111 Cases 10 Cases operation clamped for two hours. The patients position was varied every few to ensure the contact of the drugs over the entire pleural minutes cavity. The chest tube was reconnected under and 15 cm of constant water suction drainage tube was removed when the cated full reexpansion of the lungs. In through the chest tube was performed time for removal ofthe was water-sealed used. chest effusion. intercostal roentgenograms lung mdi- Results of investigation effusion showed that 157 of positive for tumor cells (78.5 of the pleura was performed with 12 positive results (55. results of cytologic investigations pleuroscopy was and performed Disappearance ofrumor Effusion The with results Survival oftreatment the pleural needle in nine eight positive pleural biopsies; surgical procedures was performed positive of open and with biopsy during in ten cases with Control in Relation in 183 patients Table 5-Treatment the drugs 50 percent was did Effectiveness antineoplastic to treat malignant have ability those responding in patients with lesions (p<O.O1). 85) in specific to cause space, doses. chest drugs have been pleural effusion. antitumor pleural activity sclerosis and doses used were the A local combination tube drainage provided and Survival Time used in Although and also obliterasame as chemoin 103 (Chemotherapy) LC in Metastatic Pleurisy (%) Survival lime (n local cancer secondary Time Survival Number metato in primary Survival of and Agents (%) Pleurisy primary on average and Various attempts instillation cases. received in Primary of to Instilled drugs pleural chemother- local in both Relation the receive to metastatic tion of the pleural the usual systemic therapy along with to Treatment Effectiveness due metastatic ofsystemic not was 11.3 months and 11. 7 months these of Pleural who of pleural evaluated as of 183 primary and the effectiveness who Treatment biopsy cases in Table to therapy. in patients have Time thirty-seven apy pleurisies results. Cells responded therapy patients, the 200 effusions were percent). Needle biopsy 22 times in 18 patients 5 percent). When the failed, 100 percent hundred static pleural patients. The survival time Investigations cytologic decrease weeks was mesothelioma In contrast, drain. of Cytologic One cancer, effusions some cases, thoracography to evaluate the appropriate RESULTS Results immunothera- are listed effective treatment according to the Japan Lung Cancer Society. In our protocol, significant decrease constitutes a 75 percent decrement in treated pleural drainage, The drugs, materials Disappearance or significant fluid stable fur more than four (Av 16 days/pt) Surgical ofantineoplastic or sclerosing (Months) Number (n = 55) lime (Months) Systemic Chemotherapy Systemic Only 9 50.0 3.9 7 50.0 4.0 28 18 4 4 79.0 67.7 85.0 75.0 14.8 7.8 10.6 9.5 15 10 4 5 90.0 12.8 19 85.0 14.0 3 80.0 12.0 Chemoth. + Local Chemoth. MMC ADM MMC+ADM MMC+5FU CQ+5FU Others 394 Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 75.0 5.0 60.0 10.0 8 95.0 100.0 11.2 10.3 6 80.0 13.5 Treatment of Malignant Pleural Effusion (Reshad et a!) Table 6-Treatment Effectiveness and Survival Time (Chemotherapy + Immunotherapy) u: in Primary Pleurisy in Metastatic (%) Pleurisy (%) Survival Number . (n Survival lime = 38) (Months) Number (n lime = (Months) 21) MMC+OK432 16 83.4 12.2 9 71.5 12.0 ADM+OK432 10 55.0 6.2 5 75.0 7.0 3 67.0 8.0 MMC+ADM +0K432 2 75.0 7.5 +OK432 4 90.0 9.8 1 88.0 11.3 6 67.7 4.5 3 67.7 5.0 Others OK432 Table 5 shows vival time ofl4O drugs by those who local the treatment patients, who local instillation received instillation was drugs by compared cancers and with without ofprimary successful instillation in combination 85 to 100 percent significant two groups resingly Treatment was obtained of primary effusions, respec- The type median months months survival ranged in pleurisy of primary in cases with metastases. In contrast, percent the with periods 3.9 in patients apy only. The No who received in survival (5) 67 Sguanoa to 14.8 shown and 5.0 to 13.5 adenocarcinoma chemotherapeutics, was median systemic time between of FIud Swv,,.I T.,oo 72 ca :: Large Small cell ca cell Ca, Alveolar Ofh.,s 5 0 1 0 3 0 Musofit 5 IIS 74.0 83.0 83.0 : : : :: fstoIogy C (Monfhs) ? of - 23 Gtro-InfL I. u1.,o-.r. t 20 , oo .o 80 .0 :‘ 75.2 f. 3 primary instillation or sclerosing of pleural fluid becom- (73.5 percent) and pleural (72 percent). The P FId (%) 85 .0 82.0 Sun,,val Tims 5 10 15 2O survival time .0 73.5 (pri- .0 50.0 : 67 7 !iii -:-- 50.0 50.0 FIGURE (metastatic . 50 -;SS 2. .0 -:--- 50.0 : :: 81 .0 Effectiveness of tumors, 65 patients). SSN1 50.0 50.0 1 77.8 local treatment and CHEST I 88 I 3 I SEPTEMBER, Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 (Monff) . I. Total time 85 50 0th.,. survival cases). (%)CII,, -:- Lh. K. and five is with in the in 48 patients 80 Swcanu .7 patients 20 M.t Th 67 to tumor methothelioma D_Pfrt#{149}n s.o Munnry : intra- f. .7 cells disappearing c__ .0 1. Effectiveness of local treatment cancer, 113 cases; mesothelioma, lung tumor No a sys- 100.0 67 in local Thyroid 1 !_ ._: Toi.I 0 77.0 Time a these according and seven in 49 patients D.cr Pt Survival cancer 1. Sixty showed was also between treated with local immunotherapeutic negative effusion 019 24 cell agents ing chemother- 10 :: 50 survival time treatment lung in Figure 7.8 those who received only was significant (p<O.00l). treatment according to D,sp#{149}tancs of Too,o, Cells of months to local primary from effectiveness 4.0 to c!! Adsooca,. treatment and P4stoIogy cancer and difference treated pleurisy temic chemotherapy The response FIGURE period improve- there Type response in and whose tumor. better alone, in survival to Tumor 55 to 90 metastatic showed Effectiveness Relation to instilled difference (p<0.01). is in in 21 patients secondary OK432 agents agents from varied percent combinations than of these patients to 88 was all rates effectiveness cancer 67 effusion of (p<O.Ol). The lung ment anti- 6. The and pleurisy therapeutic of MMC pleural primary Although cancer ofmetastatic chemoimmunotherapeutic in Table pleural instillation metastatic instilled shown percent (16 cases). intrapleural and CQ plus 5FU therapy in 79 to 90 percent and mary 38 in 75 to 100 percent neoplastic agents. More sponse with intrapleural tively cases), chemotherapy in 67 to 85 percent and obtained lung pleurally (124 systemic of the Improvement patients effectiveness and surreceived antineoplastic 1985 395 0 50 Ag. Survn#{149}I (v.0.) S $2 Pisuro LC 0 7. 6 ‘9 0 10 Tuv 19 (tne.) 20 25 30 35 It t Ad - Pnitrt MPt 0 $7 mesothelioma One patient denly one and three months month after 0 two to last patient pleurodesis subjected to lobectomy and surgery. after of malignant pleural SSSSSt 0 S The were C surface cotomy R two patients operation. of this high mortwo patients Mitomycin Pati. the undersud- died survived for eight months. Because tality rate after pleuro-pneumonectomy, recurrence LC S. surgery, after ten and 24 months after six, ten, 18, 36 months S Moth + PI#{149}ursd #{149} and one with malignant pleuropneumonectomy. after decortication ofthe pleura, and four patients to partial resection of the tumor with pleurodesis. Two patients who received partial resection with pleurodesis died Ad Lob.ct cancer went effusion and was to prevent Four patients this procedure are alive with no (Fig 3). OK432 insufflation per!brmed during the recurrence over the open thora- of malignant pleural effusion. Ad DISCUSSION PIured. ::#{149} #{149} .7 Drugs IrIiod t MMC Infvapl,ueaIly 10 01(432 3. Surgical FIGURE effectiveness of tumor was 83 percent tively. 0 mg 20 kE percent in pleurisy. shown in other The mean large cell types ofpnmary survival time the venous by disappearance of pleural fluid cell carcinoma, carcinoma, and malignancies was 17 months tive effusion continued tumor fluid. cells On tumors. in pleural the effusion whole, the time Surgical Effusion was 11.7 Procedures in has been with empyema tion or secondary 20 percent of the from this malignant procedure pleural cells and heart cases after of the patients the the mean Pleural shown malignant after other air leakage, decreased pulmonary failure complicated postoperatively, is also effusion, leads to trolled func- of and patients with with primary lung Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 malignant advocated for Each therapy has so it is difficult depletion, high Tube with is risk thoracotomy especially agents, Sayenk’ malignant a much reported pleural cotomy has success in 90 percent such been of with instillation more of effective Pugh,4 and by Nitrogen and Jones5 Treatment initial have reported used most effusion. of pleural been pleural effuet al,3 Borja success- instillation has been tumors, results of talc thora- sclerosing tetracycline and malignant control metastatic successful conat the with Other of malignant results. Rocklin quinacrine mustard powder intruded Jones2 of patients. Hickman with talc when Also, insufflation surface through a tube as quinacrine ful treatment pleurally. that effusion described various achieved Four three to effec- often is most beneficial to the accepted that repeated to other forms of therapy etc. evacuation, types the treatment of reported complete high. too therapies protein time of open thoracotomy. powder over the pleural and of mechanisms. respond effusion. and mortality, lung, more than and mortality 396 but administered for treatment sion with good to excellent effusion methods bleeding, pleural method. agents to be highly pleural usual may to be various trapped Adler in 54 the which therapy is now generally is inferior it different of pleural disappeared Malignant who experienced recurrences treatment. However, persistent pneumonia, decrease and in 49 of65 or decreased; Against patients survival months. Pleuropneumonectomy effective median was 18. 2 months disappearance and tumor of65 patients (81. 1 percent), pleural effusion disappeared survival The cancer patients with 85 percent because infection, to 70 illness. intractable. continue the treatment ofmalignant some level of morbidity respecin small 50 of the invasion of the pleura of lymphatic and effusion chemotherapy, remains There 67.7 complica- in of malignant probably pleural systemic secondary to metastatic is a common occurring the course pathogenesis are malignant to determine patient. It thoracocentesis in 23 breast instillation, exact channels Some cell carcinoma, with the longest survival time 58 months. The mean survival time was 11.3 months on average in all patients with primary cancer pleurisy. Figure 2 shows the effectiveness and survival of local instillation ofdrugs in 65 patients with pleural effusion time drug effusion malignant diseases, of all cancers in effusion is often obscure, direct by tumor cells and obstruction for carcinomatous treatment pleural Although 20 cells and significant decrease and 74 percent in squamous 77 both therapy ofthe tion of percent . Ld 3 Malignant intra- frequently Kinsey effusion in et al6 from and Leininger et al7 in 90 percent of patients of Malignant Pleural Effusion (Aeshad et a!) with the instillation pleural space through of nitrogen mustard a tube thoracotomy, but into the Ander- son and coworkers8 obtained poor response with intracavitary administration of this drug in lymphomatous pleurisy. Adriamycin, mycin several carbazilquinone, and 5FU authors excellent. cadia CWS were been was in Immunotherapeutic or OK432 were 15 out Norcadia reported 27 months when reported were obtained series, these of 18 CWS and cavity percent malignant than this the improvement given with after other methods the obtained in up to 90 percent sies and up to 100 percent and received chest drainage with were cancer pleuritumors, who local therapy. obliteration the delay We obtained resection sion patients ineffective, definitive pleural effusion, was frequently excellent with a majority who failed trapped to have lung the responsible initial pleurodesis in whom but when for patients results of patients due pleural methods is too radical with may Also, to effusion pulmonary protein possibly a careful or treatment function, depletion or infection ofmalignant and pleural talc. effusion: Thor Ann Surg A 1976; ‘freatment ofrecurrent Thorax 1969; Smart CR, DB, malignant Gynecol pleural Wagner DE, effusions Obstet effusion by iodized talc 24:69-76 using 1964; Silvia ARM. quinacrine Control of hydrochloride. 118:991-94 local instillation of quinacrine (Mepacrine) hydrochloride. 1970; 25:226-29 6 Kinsey DL, Klassen KP, Carter D. Simplified management of malignant pleural effusion. Arch Surg 1964; 89:389-92 7 Leininger BJ, Barker WL, Langston NT A simplified method for management of malignant pleural effusion. J Thorac Cardiovasc Surg 1969; 58:758-63 8 Anderson CB, malignant 9 Ohta Philpott effusions. M. GW, Cancer Treatment 10 Leff A, Hopewell nancy, Ann Intern 11 Ferguson 1974; TB. The treatment of 33:916-22 of pleural effusion. Geka to lung 1982; MOOK K, Kitano M, Hitomi N, Bans MS. Beattie S. Treatment malig- Indications agents. Jap J for pleurectomy 1975; 35:734-38 K, Shinkai T, Shimizu E, Shibuya 14 Nagao special K. trial using NCWS in treatment of malignant Gann to Kagakuryoho 1983; 10:290-95 Studies on treatment of pleural cinomatosis, with reference to effect of 0K432. Chiba Med J 1982; 58:345-53 15 Ohta K, Oyama A, Kurita 5, Nishimura M, Ogawa M, Kamei Y. Effect ofhemolytic streptococcal preparation OK432 on pleuritis and peritonitis carcinomatosa. Gann to Kagakuryoho 1980; 2:255-65 16 Egawa malignant 17 N, Meguro Izbicki R, Weihing Pleural effusion 18 Takagi T Local efflisions. K. Cases pneumonectomy. instillation Shindan BT, in cancer ofpleural Japan to Shinyaku of0K432 1982; in treatment of 19:201-04 Caoili EM, Vautkevicius VK. Cancer 1975; 36: 1511-18 carcinomatosis undergoing panpleuroJ Lung Cancer 1981; 21:161-75 Baker L, patients. CHEST I 88 I 3 I Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 from of carcinomatous of anticancer EJJr. in malignant effusion. Cancer Saijo N, Eguchi K, Tominaga effusion A. A randomized pleural effusion. effuwere and malignant Reshad PC, Costello J. Pleural Med 1978; 88:532-37 pleurisy and pleural permeability Lung Can 1982; 22:139-51 reason. in definite in malignant other treatment this procedure which cases. 4 Borja RR, Pugh RE Single dose quinacrmne (Atabrine)and thoracotomy in the control of pleural effusions in patients with neoplastic diseases. Cancer 1973; 31:899-902 5 Hickman JA, Jones MC. Treatment ofneoplastic pleural effusions 13 instillation of M MC combined with and CQ plus 5FU. Also, we achieved successful results in most of the patients who had a short interval between diagnosis and local therapy. In of the GR. 12 Martini with intrapleural any other agent in most of instillation of antiagents in treatment be performed. 3 Rocklin Multi- ple drug instillation into pleural space was more effective in obliterating pleural fluid than single agent instillation. There was a high response rate obtained contrast, we recomconsisting 25:114-21 complications. treatment results of primary in metastatic the method effective with action local to mostly Thorax results in 90 percent, but the mormethod is about 10 to 20 percent for the high incidence of postoperative In our series, successful is 22:8-15 with pleural of treatment, approach effusion effusion, in subacute failure, where Consequently, 1 Adler RH, Sayenk I. Treatment method using tube thoracotomy Surg stalL to be a highly malignant general immediate contributing as decreasing heart should recurrent with with in the mortality. and search for factors of effusion such pleurodesis. in 30 to intrapleurally patients and situations of the symptoms, should be highly of malignant pleural prevent trapped lung pleural of patients controlled hazard to hospital has been shown for tube for alleviation for treatment aggressive for failed. pleural chest tube drainage and neoplastic or immunotherapeutic successful from therapy mend kept since malignant low morbidity in in properly selected patients.’8 Martini et al’s this procedure in patients who had recurrent effusion palliative selected be have REFERENCES results in our However, the use of radioactive in ordinary hospitals and may a radiation obtained tality into percent were that, of in patients period isotopes P Pleuropneumonectomy pleural survival Sixty effusion and efl#{232}ctive treatment for treatment ofthe patients to give study by Izbicki et isotopes is not available constitute instilled conclude secondary period survived We treatment 2 Jones reported drainage who have survival case was locally median of cases. pleural 90 efluision per!brmed median Nagao.’4 Successful in up to 90 percent been by to et al’s and results ob- (83 percent), intrapleurally effective of radioactive has pleural The most with a longer reports. Instillation Ohta initial patients instilled ‘ the 0K432 by as bleo- agents such as Norinstilled via the intracavi- al,’3 Nagao,’4 Successful by Saijo. six months C, instilled into the pleural cavity with results varying from good tary route by Saijo et Egawa and Meguro.’6 tamed received mitomycin pleural effusion, it should conservative approaches SEPTEMBER, 1985 397