Diagnosis and treatment of malignant pleural effusions

CancerTreatmentReviews(1987) 14, 107-118

Diagnosis and treatment o£ malignant pleural effusions Ian S. Fentiman Clinical Oncology Unit, Guy's Hospital, London SE1 9R T, U.K.

Introduction Pleural effusions commonly complicate malignant disease, either as a manifestation of recurrence or as the first presentation of cancer. Although usually signifying inoperability of solid tumours, it is possible to achieve long periods of palliation by appropriate therapy. For many patients, such treatment can be local rather than systemic so that little toxicity is experienced, and subsequent use of chemotherapy is not compromised. Since the extensive review by Friedman and Slater in 1978, there have been several important developments in the diagnosis and management of this condition (15). The widespread development of monoclonal antibodies raised against tumour-associated epitopes has implications for both the diagnosis and possible treatment of pleural effusion. Several new approaches have been proposed for the treatment of effusion, including shunts and intracavitary use of biological response modifiers. In addition there has been a burgeoning of controlled clinical trials which have enabled the respective efficacies of the majority ofintracavitary treatments to be compared. This review will focus on recent developments in the diagnosis ofpleural effusion, analyse the most effective and least toxic methods of palliation, and suggest a management scheme, together with a proposed system of assessment of response to intracavitary therapy.

Diagnosis The investigation of patients with known malignant disease under the care of oncology clinics will be considered, rather than the workup and differential diagnosis of patients with pleural effusions seen in chest clinics. The usual clinical presentation is dyspnoea which may be associated with a cough with or without pleuritic or dull chest pain. If the clinical signs support the diagnosis ofa pleural effusion this can be shown radiographically and the presence of free fluid confirmed by a shift in opacity on the lateral decubitus view. An early asymptomatic effusion may be discovered by routine post-treatment radiographs ordered as part of follow-up protocols for patients in controlled clinical trials. Although this assists in the dating of relapse, there is no evidence that early treatment of an asymptomatic effusion is of value. The distribution of primary tumours responsible for pleural effusions will largely depend on the specific interests and referral pattern ofoncology clinics. A recent review of diagnoses from a general cytology department reported that 10% of effusions contained malignant 0305-7372/87/020107+ 12 $03.00/0

© 1987AcademicPress Limited 107

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I.S. FENTIMAN

cells (25). There were sex differences in primary sites. For males the order of frequency of primaries was lung (49%), lymphoma/leukaemia (21%), gastrointestinal (7%) and genito-urinary (6%). In contrast the commonest female primary was breast (37%), followed by genital tract, mainly ovary (20%), lung (15%), lymphoma/leukaemia (8%) and gastro-intestinal (4%).

Thoracentesis

It has recently been suggested by the Health and Public Policy Committee of the American College of Physicians that diagnostic thoracentesis should be an essential step in the workup of patients with effusion, unless there was an obvious cause such as congestive cardiac failure (18). The procedure is safe, the only major contraindication being a clotting abnormality or a low platelet count (30).

N a t u r e o f t h e e f f u s i o n fluid

Malignant effusions are typically exudates with high protein content and elevated levels of lactate dehydrogenase. However, neither of these features is of sufficient specificity to make a confident diagnosis of malignancy. The only unequivocal proof is the presence of malignant cells, identified after cytospin and pellet staining by the Papanicolaou method. However, even under circumstances where the effusion is of malignant aetiology, positive cytology can be obtained in only 60%. This pick-up rate may be augmented by 7% ifpleural biopsy with Abrams or Cope needle is performed at the time ofthoracentesis (45). Both thoracentesis and pleural biopsy are widely available procedures. In contrast, not all centres will have access to thoracoscopy, which may be a useful adjunct to the diagnostic workup of suspected malignant effusions. Thoracoscopic evidence ofparenchymal pleural deposits may be seen in 60% of cases in whom pleural cytology is negative. (12) In addition, thoracoscopy can be used to biopsy posterior parietal pleural tumour nodules which might not be found on blind needle biopsy of the pleura. Another advantage was that sufficient material for steroid receptor measurements could be obtained from endocrine-responsive tumours. However, newer techniques of receptor assay allow this to be performed on cells from pleural fluid (8). Neither cell culture techniques nor flow cytofluorimetry have been found to contribute to an increased pick up of malignant cells (46, 47). Use of Ca-2, Ca-3, (6) and HMFG-2 (16) monoclonal antibodies has enabled slight improvements in the diagnostic yield of effusion secondary to tumours of ovary, breast and colon. A variety of putative tumour markers have been assayed in effusion fluid to try to differentiate between those of benign and malignant aetiology. O f these, the most extensively studied protein is carcinoembryonic antigen (CEA). Taking levels of greater than 5 ng/ml as being abnormal, the measurement of CEA in effusion fluid has an overall sensitivity of 50% and a specificity of 80% (28, 32, 37, 40, 49). It has been claimed that the combined use of CEA levels, together with concentrations of the acute phase protein anti-chymotrypsin (ACT) may give a better discrimination between benign and malignant effusions (49). Another acute phase protein, alpha 1 acid glycoprotein (AGP), has been

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reported to be elevated in malignant effusions, although adding little to CEA value (32), but others have found higher levels of AGP in benign effusions of tuberculous origin (37). Because there may be an increased synthesis of prostaglandins in carcinoma cells (4), levels of prostaglandin E have been measured by radio-immunoassay in effusion fluid and plasma from patients with benign and malignant effusions (22). Although prostaglandin E was found to be elevated in exudates, there was no correlation with pleural fluid protein levels, nor with plasma levels.Thus this cyclic fatty acid does not appear to be of value as a discriminant between malignant and benign effusions. Measurement of enzymes such as lactate dehydrogenase (LDH) (42), phosphohexose isomerase (PHI) (32) and lysozyme (53) have not been found to distinguish between malignant and nonmalignant effusions. Thus none of the presently available tumour markers are of sufficient specificity to eliminate a malignant aetiology for an effusion in which no malignant cells have been detected cytologically. Therefore patients with symptomatic pleural effusions which are clinically suspected to be of malignant cause should be treated by effective intracavitary therapy, even if no malignant cells have been identified.

Prognosis The determination of prognosis and hence the need for active local treatment of an effusion depends upon several factors including age, performance status, primary tumour type, pattern of metastatic disease and overall tumour burden. Wide variations have been reported in the median survival after diagnosis of an effusion in patients with various primary tumour types. Breast cancer patients have the longest survival, with broad agreement that the median life expectancy is greater than one year (11, 33, 43). The survival of lung cancer cases with effusions varies with histological type, but the median survival is 6 months (3, 33). No large body of data exists for patients with gastrointestinal and ovarian primaries but the probable survival after effusion is between 6 months and one year (43). For patients with non-Hodgkin's lymphoma, where treatment of pleural effusions is systemic rather than local, it has been found that the median survival of those whose effusions disappear was 40 months compared with 6 months for those with persistent effusions following systemic therapy (54). It has been claimed that the pattern of intrathoracic disease may affect the prognosis but in a prospective randomised trial in which all patients were thoracoscoped,there was no correlation between outcome and distribution of intrapleural tumours (13). It could be predicted that patients with rapidly growing tumours would have a worse prognosis. Based on this premise, Hostmark measured the cell cycle distribution and ploidy of effusion cells by flow cytometry (19). Although an aneuploid DNA histogram was associated with the presence of malignant cells, the survival of patients with diploid and aneuploid DNA did not differ significantly. Present techniques for determining the prognosis are very imprecise. Taking just the reported clinical trials of treatment, in which by definition the authors had an interest and expertise in management, there is a mean early mortality rate of 17.6% (12.8-22.4), 95% confidence interval); almost one in five of these patients died within 1-2 months of treatment.

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I. S. FENTIMAN Cause of effusion

The normal physiology ofpleural fluid secretion and absorption has been clearly reviewed by Black (5). In effusions secondary to malignancy, the most likely aetiology is a failure of absorption. This may result from intraparenchymal lung tumour, lymphatic obstruction by metastases, or occasionally cardiac tamponade resulting from pericardial effusion. Pleural effusions secondary to pericardial fluid may respond to pericardiocentesis without a need for intrapericardial sclerosants or pericardial window formation (52). Similarly, where the effusions are secondary to superior venal caval obstruction by tumour, a course of external irradiation to the site of obstruction may enable resorption of the pleural fluid, althouth a direct approach to the pleural effusion may be necessary. Once causes such as pericardial effusion, SVC obstruction, cardiac failure, or reduced plasma osmotic pressure due to cachexia have been excluded, there is little value in further investigating patients sihce their treatment will probably be unaffected by further knowledge of the pathogenesis of the effusion.

Assessment

of response to treatment

No internationally agreed system of response assessment is in use for the evaluation of pleurodesis techniques. A variety of assessment systems have been employed which have included subjective response, clinical judgement, chest radiography and varying lengths of follow-up. Some principles should be stated for any system of assessment. First, the aim of pleurodesis is palliation of the symptom of dyspnoea. This may of course be achieved without a complete disappearance of pleural fluid but nevertheless, in the comparison of techniques which try to achieve pleurodesis, the most efficient agent should be determined and this will bear a relationship to the completeness of pleural fusion and hence absence of recurrence. Secondly, because of the subjective nature ofdyspnoea, the usual categories for assessment of active disease, complete response, partial response, stable disease and progression are not appropriate. For example stable disease may be associated with pesistent symptoms and thus will be a failure of palliative treatment. Clinical evaluation of fluid recurrence may be inadequate and thoracic clinical signs may be greatly changed by pleurodesis. It is proposed that three categories of response be adopted. These should be based on radiographic follow-up, with the immediate post-aspirational chest radiograph being used as a baseline. Complete response--No reaccumulation of fluid from treatment to death, or last followup. Partial response---Asymptomatic recurrence of fluid with no requirement for treatment. Failure---Symptomatic reaccumulation of fluid on chest radiograph.

Treatment

Intracavitary radio-isotopes One of the originally proposed intracavitary therapies for malignant effusions was radioactive gold (2). Although a reasonably effective technique, this did pose formidable

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problems in relation to radiation protection of the patient and medical and nursing staff. It has now been widely appreciated that the mechanism of action was sclerosant rather than directly cytotoxic. Development ofmonoclonal antibodies such as HMFG-2 which recognises epitopes on malignant cells from the breast and ovary led to the use of these proteins for cancer cell targeting. Encouraging results have been reported after intracavitary administration of I TM labelled H M F G 1, H M F G 2 and AUA1 to patients with malignant pleural and ascitic effusions (39). It has not yet been determined how much the efficacy of this treatment relates to specific tumour binding and how much to non-specific retention of isotope within the pleura or peritoneum.

Intracavitary biological response modifiers Immunomodulatory agents have been administered intrapleurally to prevent effusion recurrence. The streptococcal preparation O K 432 produced a major increase in large granular lymphocytes which lysed autologous tumour cells in vitro (48). In association with this, 80% of patients given intracavitary O K 432 manifested a decrease in effusion volume together with either reduction or elimination of malignant cells within the effusion fluid. BCG cell wall skeleton was given intrapleurally to 26 patients with malignant effusions (44). Partial response was achieved in 32% but complete control in only 14%. However, in 28% of cases there was an increase in fluid formation; pyrexia developed in 40% and pleuritic pain in 38%. The combination of low efficacy and high toxicity make BCG a less than ideal intracavitary agent. The non-specific immunostimulant Corynebacterium parvum has been used in several uncontrolled studies with effective pleurodesis being achieved in 80% (CI 58.3-101.1) (7, 10, 34, 50). In addition to achieving local control it has been claimed that Corynebacterium parvum has systemic activity with a prolongation of overall survival in patients receiving this therapy. However, this additional benefit has yet to be confirmed in a prospective randomised controlled trial, although the agent has been tested in this manner (29, 36). The interferon group of regulatory proteins are involved in cellular antiviral responses, and have also been found to have antineoplastic activity against cancers such as hairy cell leukaernia and renal cell carcinoma. This action may result not only from a direct antitumour effect but also from stimulation of NK cells and macrophage activation. Two studies have been reported in which intracavitary leukocyte interferon (alpha-interferon) was administered to patients with pleural effusions, with apparent good control (20, 23). More recently interleukin-2, the lymphocyte second signal for mitogenesis, has been given intraperitoneally to patients with disseminated melanoma, and ovarian and colorectal carcinomas (31). This produced a marked increase in peritoneal exudate cells, particularly T lymphocytes. This was achieved with side effects including fever, chills, nausea, vomiting and major weight gain due to capillary leak syndrome. Before this technique could be used in the management ofpleural effusion, a major advantage would have to be shown compared with standard techniques, in order for the toxicity to be acceptable.

PIeuro-peritoneal shunts There have been a few case reports and small series in which malignant pleural effusions have been managed surgically by insertion of pleuro-peritoneal shunts of the Levene type

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I.S. FENTIMAN

(9, 41, 51). This procedure can be performed under local anaesthesia. The afferent limb is inserted into the pleural space, the reservoir located at the costal margin and the efferent limb placed in the peritoneal cavity. Although this mechanistic approach may be of value in certain rare circumstances, the majority of patients with malignant pleural effusions can more simply be managed. The procedure carries the theoretical risk of dissemination oftumour within the peritoneal cavity, although this complication has not been reported.

Controlled trials of intracavitary therapy The majority of the commonly used intracavitary agents have now been tested in controlled randomised trials. The numbers ofevaluable patients, design of trials, and results are given in Table 1. Non-evaluable cases resulted from early death (within 4--6 weeks) before treatment could be assessed, which has been previously discussed. Where patients received more than one treatment, the actual number of cases is shown in brackets. The mix of primary tumours has been shown in the first column giving numbers for the three commonest causes namely breast (B), lung (L), and ovary (O). The remaining primary tumours (R) are given as a total. The technique of assessment usually used, either success/failure or complete response/ partial response/failure. With the latter system a few authors added the category 'static disease'. Within the results section, both complete response and partial response or static disease have been combined as success although some investigators using the more stringent success/failure system would have described partial response (that is reaccumula~ion without need for re-treatment), as a failure. O f the treatment methods examined, the least effective was intracavitary thiotepa which produced effusion control in only 27% of cases (35). This appeared to be slightly less effective than drainage alone which controlled 37% (17.6-57) of effusions (21, 35, 38, 47). Figures in parenthesis are 95% confidence limits. Intracavitary mustine was also of some value, controlling 48% (45-50) of malignant pleural effusions (13, 26, 36). One possible explanation for the inefficacy may be that there is a rapid transpleural flux of these agents, resulting in systemic absorption, with side effects such as nausea, but with too brief retention in the pleural space so that sclerosis is not achieved (13). For the majority of the other agents a broadly similar control rate was achieved: quinacrine 62% (60-64) (3, 35), tetracycline 66% (61.5-69.5) (3, 14, 17, 24, 26, 27, 29, 38, 55), bleomycin 67% (56.8-77) (17, 24, 26) and adriamycin 73% (26). However, two agents, neither of which are directly cytotoxic, emerged as superior. These were Corynebacteriumparvum and talc, which controlled 94% (87.5-99.9) (29, 36) and 94% (9096.8) (13, 14, 47) of effusions respectively. Thus these sclerosants appear to be the treatments of choice for malignant effusions, although it should be said that the talc results are derived from three separate trials, whereas the Corynebacteriumparvum data are from two studies. Tables 2 and 3 give the results of treatment trials ofintracavitary therapy for malignant effusion secondary to breast and lung cancer, where these have been specified by authors. Because of the smallness of numbers the results of treatment of pleural effusions secondary to ovarian carcinoma have not been given. Broadly similar results have been achieved in the control of effusions due to either bronchial or mammary malignancy. Although both Corynebacteriumparvum and talc can be administered via an intercostal tube to a conscious patient, as an office procedure (3), the majority of surgeons prefer to

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Table 1. Overall results of controlled trials of intracavitary therapy for malignant pleural effusions B

T u m o u r types O L R

Total evaluable

49

4

4

10

67

7

0

8

10

38 (25)

9

3

3

5

1

1

13

3

20 •

NS

18

30

NS

29

7

6

3

9

25

9

0

6

7

22

37

0

0

0

37

l

NS

62

NS

21

0

19

12

32

Response F %

Treatment

S

Reference

Drainage v Drainage 32p Drainage v Quinacrine v Thiotepa Tetracycline v Quinacrine Mustine v

17

39

44

21

17 1

28 9

61 11

35

9

14

64

4 8

15 t0

27 80

3

6 5

10 11

60 45

36

C. parvum

7

7

100

Mustine v Adriamycin v Tetracycline Drainage v Tetracycline Bleomycin v Tetracycline pH 2.8 v Tetracycline Mustine v Talc Bleomycin v Tetracycline Drainage v Talc Tetracycline (needle)

4

9

44

8

lI

73

7 4

10 11

70 36

38

13 7

18 13

72 54

17

7 1

12 9

58 11

55

9 9

13 17

69 53

13

18 27

20 31

90 87

24

18 7

31 12

56 58

47

9 5

9 9

100 56

29

6

7

86

14 10

16 16

88 65

27

9 10

15 21

62 48

14

11

12

92

26

v

Tetracycline (tube) v

C. parvum NS

33

0

31

0

0

33

Tetracycline v Bleomycin Tetracycline v Talc

Column 1 gives mix of primary tumour types, B = Breast, L = Lung, O = Ovary, R = Remainder, NS = Not Specified. Column 2 shows number of evaluable cases. Where more than one treatment was given actual numbers of cases are in brackets. Column 4 shows method of assessment of response to treatment. S = complete response and/or partial response and/or static disease, F = failure.

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I.S. FENTIMAN

Table 2. Results of trials of intracavitary therapy for pleural effusions secondary to breast cancer Response F %

Number

Treatment

S

52

Drainage v Drainage + 32p

15

15

50

12

10

54

1

2

33

3

1

75

10

Drainage

Reference 21

35

v

Quinacrine V

10

Thiotepa

2

1

67

Tetracycline

5

2

71

3

v

Quinacrine

2

1

67

1

Mustine v C. parvum

0

0

0

1

0

100

37

Mustine v Talc

9

8

53

18

2

90

12

pH 2.8 v Tetracycline

2

3

40

3

4

43

33

Tetracycline v Talc

10

11

48

11

1

92

36

13

55

14

Table 3. Results of controlled trials of intracavitary therapy for pleural effusions secondary to lung cancer Response F %

Number

Treatment

S

16

Drainage v Quinacrine v Thiotepa

0

4

2

5

40

2

7

29

Tetracycline

3

4

75

3

Quinacrine

0

1

Mustine

4

9

44

36

C. parvum

7

7

1O0

p H 2.8

1

5

20

4

6

67

5

Reference 35

v

16

v

11

v

Tetracycline

55

MALIGNANT PLEURAL EFFUSIONS

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perform talc poudrage under general anaesthesia because of the severity of pleural pain induced. This requirement for general anaesthesia makes the technique unsuitable for very ill patients but it could be argued that such cases should not be treated in this intensive manner because of their presumed poor prognosis. Even in relatively fit patients, a general anaesthetic does pose formidable problems and it is therefore essential that an anaesthetist experienced in thoracic management should be responsible for such cases.

Management

scheme

An outline scheme of management for malignant pleural effusions is shown in Fig, 1. Once the diagnosis has been confirmed a decision will be made on whether systemic or local therapy should be adopted. In the case of lymphomas, this treatment will almost always be systemic whereas for tumours of lung and breast, where there may not be any other symptomatic metastatic disease, the treatment will probably be local. First line treatment should comprise either intracavitary Corynebacteriumparvum or talc and the choice of agents will depend upon the facilities of the oncologist and the suitability of the patient for general anaesthesia. Using these techniques a high rate of effusion control can be expected. This can be achieved without lung entrappment or effusion loculation so that major procedures such as decortication should be rendered redundant. As has been shown in this review, effective treatments for malignant pleural effusion are available. What is lacking is sufficiently accurate prognostic information to determine which patients will benefit from pleurodesis. Future studies should be aimed at improvement in selection of patients for intracavitary therapy in order that effective techniques

J

Suspectedeffusion

I

Confirmedby aspiration

I

I

I

I

I

[

requiring treatment I

Systemic*heropy I

I

1 control

J

I

I Cytology positive [ Other disease I requiring treatment

I

[ effusion I control

I Cytologynegative ]

[ I I c(~usecause N°°fher ofund I I Terat I

I

I

Talc or Corynebacf. pleurodesis

I

I effusion I I I J Systemic therapy J J Decorticafion I

Figure 1. Pleural effusion management scheme

116

I . s . FENTIMAN

a r e g i v e n to p a t i e n t s w h o will d e r i v e b e n e f i t f r o m t h e m . T h i s m a y p r e v e n t o v e r - t r e a t m e n t o f p a t i e n t s i n w h o m t h e p r o g n o s i s is t o o l i m i t e d for a n y i m p r o v e m e n t i n q u a l i t y o f s u r v i v a l to b e g a i n e d .

References 1. Adler, R. H. & Rappole, B. W. (1967) Recurrent malignant pleural effusions and talc aerosol poudrage. Surgery 62: 1000-1006. 2. Ariel, I. M., Oropeza, R. & pack, G. T. (1966) Intracavitary administration of radioactive isotopes in the control of effusions due to cancer-results in 267 patients. Cancer 19:1096-1102. 3. Bayly, T. C., Kisner, D. L., Sybert, A., McDonald, T. S., Tsou, E. & Sehein, P. S. (1978) Tetracycline and quinaerine in the control of malignant pleural effusions. A randomised trial. Cancer 41:1188-1192. 4. Bennett, A., Charlier, E. M., McDonald, A. M., Simpson, J. S., Stanford, I. F. & Zebro, T. (1979) Prostaglandins and breast cancer. Lancet 2: 624-625. 5. Black, L. F. (1972) The pleural space and pleural fluid. Mayo Clin. Proc. 47: 493-506. 6. Bramwell, M. E., Ghosh, A. K., Smith, W. D., Wiseman, G., Spriggs, A. I. & Harris, H. (1985) Ca2 and Ca3. New monoclonal antibodies evaluated as tumour markers in serous effusions. Cancer 56:105-110. 7. Currie, J. L., Gall, S., Weed, J. C. & Creasman, W. T. (1983) Intracavitary Corynebacterium parvum for treatment of malignant effusions. Gynecol. Oncol. 16: 6-14. 8. Di Lorenzo, D., Zanboni, A., Simoncini, E., Marpigati, P., Montini, E., Alghisi, A., Gorni, F. & Marini, G. (1986) Estrogen and progesterone receptors in neoplastic cells of metastatic pleural effusion of breast carcinoma before and after tamoxifen therapy. Correlation with the clinical response. Chemioterapia 5:232 236. 9. Dorsey, J. D. & Cogordan, J. A. (1984) Pleuroperitoneal shunt for intractable pleural effusion. Can. J. Surg. 27: 598-599. 10. Felletti, R. & Ravazzoni, C. (1983) Intrapleural Corynebacterium parvum for malignant pleural effusions. Thorax 38:22 24. II. Fentiman, I. S., Millis, R. R., Sexton, S. & Hayward, J. L. (1981) Pleural effusion in breast cancer: A review of 105 cases. Cancer 47: 2087-2092. 12. Fentiman, I. S., Rubens, R. D. & Hayward, J. L. (1982) The pattern of metastatic disease in patients with pleural effusions secondary to breast cancer. Br. J. Surg. 69: 193-194. 13. Fentiman, I. S., Rubens, R. D. & Hayward,J. L. (1983) Control ofpleural effusions in patients with breast cancer. A randomised trial. Cancer 52: 737-739. 14. Fentiman, I. S., Rubens, R. D. & Hayward,J. L. (1986) A comparison ofintracavitary talc and tetracycline for the control ofpleural effusions secondary to breast cancer. Eur. J. Cancer Clin. Oncol. 22: 1079-1081. 15. Friedman, M. A. & Slater, F. (1978) Malignant pleural effusions. Cancer Treat. Rev. 5: 49-66. 16. Ghosh, A. K., Spriggs, A. I., Taylor-Papadimitriou, J. & Mason, D. Y. (1983) Immunocytochemical staining of cells on pleural and peritoneal effusions with a panel of monoclonal antibodies. J. Clin. Path. 36: 1154-1164. 17. Gupta, N., Opfell, R. W., Padova, J., Margileta, D. & Soudjian, J. (1980) Intrapleural bleomycin versus tetracycline for control of malignant pleural effusion: a randomised study. Proc. ASCO 21: 366. 18. Health and Public Policy Committee. American College of Physicians (1985) Diagnostic thoracentesis and pleural biopsy in pleural effusion. Ann. Intern. Med. 103: 799-802. 19. Hostmark, J., Vigander, T. & Skaarland, E. (1985) Characterisation ofpleural effusions by flow-cytometric DNA analysis. Eur. J. Resp. Dis. 66: 31,%319. 20. Ikic, D. (1983) Intralesional therapy. In: Sikora, K. ed. Interferon and Cancer. New York: Plenum Press, p. 169. 21. Izbicki, R., Weyhing, B. T., Baker, L., Caoili, E. M. & Vaitkevicius,V. K. (1975) Pleural effusion in cancer patients. A prospective randomised study of pleural drainage with the addition of radioactive phosphorus to the pleural space versus drainage alone. Cancer 36" 1511 1518. 22. Jenkinson, S. G. & Banschbach, M. W. (1982) Radioimmunoassay determinations of prostaglandin E in pleural effusions of various causes. Am. Rev. Resp. Dis. 126:21 24. 23. Jereb, B., Krasovec, V. S. & Soos, E. (1980) Intrapleural application of human leukocyte interferon (HLI) in brea3t cancer patients with ipsilateral pleural carcinoma. In: Proc. XIVth UICC Conference.

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