13. I~ORTSACL. H.,BENEDICT.C. R.. I-AISW. A,. SASARD.1. and McAtSsli,J. (1977): Response to atcnolol in arterial hypertension in relation 10 renal hnc:ion, pharnacnkineticc and rcnin activit?. Pmigrurl. incd J. 53 ISuppl. 31. 134 141. IS. SIIAX~. I). Ci. 11976): Pbarmauoketics of propranolol: a review. Port~rorl. iwd. J. 52 ISuppl. 4. 9 24. 19. Al.DriRMAN. E. I... C")I.IAH.I. D. J.. WLlTACll. G.k;. and HARRISUS.D.C. ( 1974): Coronary artury syndrome after aciitc propranolol withdrawal. Ann. infcw~.. W d 81. 625 627.
iI I '
I
20. Mii.i.ER. R. R..OwEa. 11. Cm.,AKS~RDAM. E.A. and YASOS.I). T. (1975): I'ropisnolol withdrawal rehound phenomena. tixacerbatioii of coronary events after abrupt cessation of antianginal therapy. ,Sm h g l . J . .Wed. 293, 416-418. 21. Wtr.cnx. R. G . (1977): Combinalioii nypotcnsivc therapy with atenolol. bendrofluazidc and hydrallaiine, Pusigrrrd. nwd. J. 53 (Suppl. 3). 128.133. 22. RAIIS. K.H..GURLICI~S, 11. W.,Prnsz. G.,PI.ANZ.K. and SWPHASY,W. (1977): The IiNmt of Propranolol on Plasma Catecholamines (Abstract). lhrop. 1. Clin. I n i n r . 6. 323. 23. OSCHAUPLAIS. J.. Ca.Sl&TAI:. D.. VANAYIIRIVG.EN.U. R.. MARC-ALP~W. 1. and YaMAc;cali. N. (1977): The role of the synpathetic system in expcrimcn:a! and human hypcrtension, P ! q w i d . iin~il.J. 53 iS-ppl. 3).
1536. 24. GR0RIX'KI.R. 11.. SAAVtl)RA. J. M..?dCcARlS 1. 1. 1 !97?); Dnpamine-B-hydr@ryiascacti
ccntrations :n plasma: experimental and css mrd J. 53 (Suppl. 3). 43 -48. 25. Ltws. P. J. (1976): The eireatinl action of pro?ranoloi in !??pertension. Anicr. J. Mi,r/. 60, X37--852.
Heparinized Chemotherapy in the Treatment of Disseminated Lung Cancer G. G. Jamieson‘ and R. C. Angovet
From the Royal Adelaide Hospital, South Australia
SUmmary: Heparinized chemotherapy in the treatment of disseminated lung cancer. G. G. Jamieson and R . C. Angove, Aust. N.Z.J. Med., 1979, 9,pp. 381-384. Fourteen patients with inoperable or metastatic carcinoma of the lung were entered in this study. All of them received one or more courses of multiple chemotherapy (cyclophosphamide, 5-fluorouracil, methotrexate and vincristine) with prior and concurrent heparin anticoagulation. No tumour regression was noted in any patient although one patient is alive and well at two years. Five patients developed sudden increase in pleural effusion whilst on heparin therapy and in four of these patients the effusion was a significant factor in their death. ~
______
‘Senior Lecturer, Department of Surgery. ‘Senior Visiting Physician. Correspondence: Dr. G. G. Jamieson. Department of Surgery, Royal Adelaide Hospital. Adelaide, South Australia 5000 Accepted for publication: 22 February, 1979
-
The place of chemotherapy in the management of lung cancer remains uncertain. It has recently been advocated as being useful’ and also to be of no benefit and indeed possibly even deleterious to the patient’s outcome.2 It has been speculated that fibrin and fibrinogen are important in the growth of tumours and also in preventing chemotherapeutic agents from penetrating through to malignant cells3 It therefore seemed logical to prevent coagulation at the tumour site with heparin, at the same time as giving cheniotherapeutic agents. Using this approach Elias, Shukla and Mink reported apparently improved results in a group of 14 patients3 We have previously used the regimen of cyclophosphamide, 5-fluorouracil, methotrexate and vincristinc in other solid tumours with disappointing results4, but other workers using this regimen have noted a partial response in six out of 14 cases with bronchial carcinoma’ and so we were encouraged to think that the addition of
heparin might further improve the results of treatment.
the basis of this report. There was no clinical evidence of cerebral metastatic disease nor any history of peptic ulcer disease in any patient. Six of the 14 patients were noted to have a pleural effusion when first seen. Table 1 shows the age and sex distribution. the extent of disease and the cell type in the 14 patients. Heparin was given before starting therapy and maintained by hourly intravenous bolus injections in order to keep the partial thromboplastin time with kaolin in excess of 120
Patients and Methods Fourteen patients with histologically proven carcinoma of the lung which had spread beyond treatment either surgically o r from radiotherapy were referred for treatment and form
TABLE 1 Patients and extent of their disease --
Cell type
M
Both lung5
Adenocarcinoma
M
One hemithorax and medidstinum
Squdmous carcinoma
M
One hemithorax
Small cell carcinoma
M
One hemithorax
Adenocarcinoma
M
One hemithorax t abdomen
M
One hemithorax
F
One hemithorax
M
One hemithorax, liver, subcutdneou\ nodules
Smdll cell cdrcinoma
M
Onc hemithorax, bone\
Adenocarcinoma
Small cell carcinoma
- bone and liver
- medidstinum and hvei
Small cell carcinoma Squamous cell carcinoma
M
One hemithorax h\er
Small cell carcinoma
E
Mediastinum, bone5 liver
M
130th tiemithoraLe$
Adenocarcinoma I.arge cell carcinoma
M
Both hemithordces
Adenocarcinoma
M
One hemithorax. livtr
Small cell carcinoma
TABLE 2 Tumour response .. ._
-_
-
Fxtent of di5ea\e
Sex
__
.
-.
'
_
..
I
-.
-
Patient
No.
A.V.
(1)
14 courses of therapy
Alive but new secondary developed whilst on therapy. Treated with radiotherapy. Therapy recently stopped at two years from commencement.
R.W.
(2)
I course
Sudden deterioration on therapy with acute massive pleural effusion leading to death.
C.H.
(3)
2 courses
Continued progression and death
G.B.
(4)
1 course
Sudden deterioration during therapy with massive pleural effusion and death.
D.F.
(5)
1 course
Continued deterioration and death.
J.C.
(6)
1 course
Massive pleural effusion. Deterioration and death after therapy
K.R.
(7)
1 course
Sudden deterioration during therapy with large pleural effusion leading to death.
S.H.
(8)
3 courses
Progression and death
W.N.
2 courses
Progression and death.
D.J.
(9) (10) (1 1)
4 courses I course
Progression and death.
M.L. A.H.
( 12)
1 course
Progression and death.
A.C.
(13)
3 courses
Progression and death.
J.T.
(14)
3 courses
Progression and death.
Course after heparinised chemotherapy ...
Sudden deterioration during therapy with acute and massive pleural effusion leading to death.
A m w r
1979
HEPAKINIZEI) CHIMOTIIERAPY I S CANC'ER
___
.~
seconds. This corresponds to a whole blood clotting time of three times normal as recommended by Elias ~t n/.3 Most patients required of the order of 1500 units to 2000 units hourly to maintain this level of anticoagulation. Chemotherapeutic agents given were as follows: cyclophosphamide 300 mgni!day on l h y b I and 5; 5-iluorouracil 7 . 5 mgm;kg!day on Days 1, 2, 3 , 4, 5; vincristine 0,015 mgm kg:day on Days 2. 5: methotrexate 0.25 mgm,kg'day on Days 1, 4. The drugs were given as a single intravenous bolus and a course was given on five days in every five weeks until either eleai- progression of disease o r death occurred. Daily PTTK and complete blood pictures were carried out and patients were not anticoagtilatcd in between courses of therapy.
Results
All patients tolerated thc chemotherapeutic regimen well and although four patients died during their first course of therapy. the deaths were not considered to be due to the chemotherapeutic agents, and apart from nausea, vomiting and alopecia there were no other drug-related side effects. The only objective evidence of tumour response was in patient number 10 who had a markedly elevated serum calcium associated with bony secondaries. The calcium fell to normal levels following the third course of therapy, but there was no overall benefit to the patient who died six weeks later following a fourth course of therapy. One patient remains alive after 14 courses of therapy. The patient had an adenocarcinoma of the left lung treated with radiotherapy and was started on heparinised chemotherapy when he developed a coin lesion in the opposite lung. There was no increase in size of this lesion during the first five courses of therapy, but then rapid growth became evident. The right lung lesion was then irradiated and the patient continued on heparinised chemotherapy for a period of t u o years. There has been no further evidence of tumour progression although the patient suffers from severe shortness of breath on mild exertion associated with radiation changes in his lungs. Therapy has now been stopped. No other patient showed any evidence of tumour regression or benefit from the heparinised chcmotherapy. Six patients were noted to have small pleural effusions prior to the commencement of therapy and in five of these patients the pleural effusions increased dramatically during therapy neces-
383
sitating pleural aspirations in all five. Only one of the five patients survived their first course of therapy and that patient died before a second course was begun. In the other four patients, one died three days after starting heparin and before chemotherapy was begun. one died five days after starting heparin and three days after chemotherapy was begun, and the remaining patient died seven days after starting heparin and five days after starting chemotherapy. All four patients became acutely short of breath with their effusions, all four had pleural aspirations (with 800 ml, 1200 ml, 1400 ml, 1450 ml being aspirated) and all four had large effusions still present at autopsy. The pleural effusions were blood stained in three out of the four patients, but in no patient was the effusion frankly bloody. Discussion
In their paper reporting on treatment for inoperable lung cancer Elias et crl. discuss the theoretical reasons for using heparin in association with chemotherapeutic agent^.^ Basically it was believed that fibrin forms an essential matrix for the tuniour and also prevents chemotherapeutic agents from penetrating the tumour. By anticoagulating the patient and preventing fibrin formation natural fibrinolysis can work unopposed and thus remove the fibrin matrix barrier. Although theirs was not a randomised study, they found no tumour regression in 14 patients treated with multiple chemotherapy alone and greater than 50:/(, tumour regression in seven patients out of 14 treated with heparin as well as chemotherapy. They reported no complications as a result of the heparin therapy. As a previous report using the regimen used in our study had shown a partial response in six out of 14 patients with bronchial cancer5, we were disappointed in our results where only one patient possibly benefited by this method of treatment. Dosages used in our regimen differed from that of Elias et al. in that we did not use 6thioguaninc and the course of therapy was used in a five-week cycle instead of a two-week cycle. One or both of these factors may have been responsible for our poorer results. Six patients had small pleural effusions at
the commencement of heparinisation and five patients developed massive increases in their effusions. So much so, in fact, that four patients died and the pleural effusions were thought to be the main precipitating factor in the deterioration which led to their deaths. The rclationship between the heparin and the pleural effusions may have been coincidental although the timing led us to consider that the heparin may have been causative. The mechanism is speculative although possibly a small fibrin rich effusion was converted by unopposed fibrinolysis to a more diffusable form. The numbers involved in this report are small and firm conclusions cannot be drawn. However, it is obvious that heparinisation is not going to convert any doubtfully efficacious chemothera-
peutic regimen into an effective treatment of disseminated lung cancer. And further, our experience indicates that heparinisation of patients with a malignant pleural effusion should be undertaken with great caution, and the patient should be observed closely for the development of a rapid increase in pleural effusion.
References I Sk.L.&wnY,0 S (1974): The rule of chemotherapy in the trcatmenl of lung cancer. Senwiors I?: 0 1 1 c o i o ~I ,i ~259 272. 2. LAN;, A. €1.. BI.RRY, K J , NIWHAV. C K.and 1 ' 1 ~ 0 ,J. (1975). 'Treatment of inoperable carcinoma of' the bronchus, [*mrrl 2, 1161~1164. 3. FLIAS. Cr. E . Sin,~l.n. S. K and MINK, 1. B (1975). Heparin and Chemotherapy in the manapcment of inoperable lung carcinoma. ('unwr 36, 129 136 4. J A M I ~ S O
iI I '
I
20. Mii.i.ER. R. R..OwEa. 11. Cm.,AKS~RDAM. E.A. and YASOS.I). T. (1975): I'ropisnolol withdrawal rehound phenomena. tixacerbatioii of coronary events after abrupt cessation of antianginal therapy. ,Sm h g l . J . .Wed. 293, 416-418. 21. Wtr.cnx. R. G . (1977): Combinalioii nypotcnsivc therapy with atenolol. bendrofluazidc and hydrallaiine, Pusigrrrd. nwd. J. 53 (Suppl. 3). 128.133. 22. RAIIS. K.H..GURLICI~S, 11. W.,Prnsz. G.,PI.ANZ.K. and SWPHASY,W. (1977): The IiNmt of Propranolol on Plasma Catecholamines (Abstract). lhrop. 1. Clin. I n i n r . 6. 323. 23. OSCHAUPLAIS. J.. Ca.Sl&TAI:. D.. VANAYIIRIVG.EN.U. R.. MARC-ALP~W. 1. and YaMAc;cali. N. (1977): The role of the synpathetic system in expcrimcn:a! and human hypcrtension, P ! q w i d . iin~il.J. 53 iS-ppl. 3).
1536. 24. GR0RIX'KI.R. 11.. SAAVtl)RA. J. M..?dCcARlS 1. 1. 1 !97?); Dnpamine-B-hydr@ryiascacti
ccntrations :n plasma: experimental and css mrd J. 53 (Suppl. 3). 43 -48. 25. Ltws. P. J. (1976): The eireatinl action of pro?ranoloi in !??pertension. Anicr. J. Mi,r/. 60, X37--852.
Heparinized Chemotherapy in the Treatment of Disseminated Lung Cancer G. G. Jamieson‘ and R. C. Angovet
From the Royal Adelaide Hospital, South Australia
SUmmary: Heparinized chemotherapy in the treatment of disseminated lung cancer. G. G. Jamieson and R . C. Angove, Aust. N.Z.J. Med., 1979, 9,pp. 381-384. Fourteen patients with inoperable or metastatic carcinoma of the lung were entered in this study. All of them received one or more courses of multiple chemotherapy (cyclophosphamide, 5-fluorouracil, methotrexate and vincristine) with prior and concurrent heparin anticoagulation. No tumour regression was noted in any patient although one patient is alive and well at two years. Five patients developed sudden increase in pleural effusion whilst on heparin therapy and in four of these patients the effusion was a significant factor in their death. ~
______
‘Senior Lecturer, Department of Surgery. ‘Senior Visiting Physician. Correspondence: Dr. G. G. Jamieson. Department of Surgery, Royal Adelaide Hospital. Adelaide, South Australia 5000 Accepted for publication: 22 February, 1979
-
The place of chemotherapy in the management of lung cancer remains uncertain. It has recently been advocated as being useful’ and also to be of no benefit and indeed possibly even deleterious to the patient’s outcome.2 It has been speculated that fibrin and fibrinogen are important in the growth of tumours and also in preventing chemotherapeutic agents from penetrating through to malignant cells3 It therefore seemed logical to prevent coagulation at the tumour site with heparin, at the same time as giving cheniotherapeutic agents. Using this approach Elias, Shukla and Mink reported apparently improved results in a group of 14 patients3 We have previously used the regimen of cyclophosphamide, 5-fluorouracil, methotrexate and vincristinc in other solid tumours with disappointing results4, but other workers using this regimen have noted a partial response in six out of 14 cases with bronchial carcinoma’ and so we were encouraged to think that the addition of
heparin might further improve the results of treatment.
the basis of this report. There was no clinical evidence of cerebral metastatic disease nor any history of peptic ulcer disease in any patient. Six of the 14 patients were noted to have a pleural effusion when first seen. Table 1 shows the age and sex distribution. the extent of disease and the cell type in the 14 patients. Heparin was given before starting therapy and maintained by hourly intravenous bolus injections in order to keep the partial thromboplastin time with kaolin in excess of 120
Patients and Methods Fourteen patients with histologically proven carcinoma of the lung which had spread beyond treatment either surgically o r from radiotherapy were referred for treatment and form
TABLE 1 Patients and extent of their disease --
Cell type
M
Both lung5
Adenocarcinoma
M
One hemithorax and medidstinum
Squdmous carcinoma
M
One hemithorax
Small cell carcinoma
M
One hemithorax
Adenocarcinoma
M
One hemithorax t abdomen
M
One hemithorax
F
One hemithorax
M
One hemithorax, liver, subcutdneou\ nodules
Smdll cell cdrcinoma
M
Onc hemithorax, bone\
Adenocarcinoma
Small cell carcinoma
- bone and liver
- medidstinum and hvei
Small cell carcinoma Squamous cell carcinoma
M
One hemithorax h\er
Small cell carcinoma
E
Mediastinum, bone5 liver
M
130th tiemithoraLe$
Adenocarcinoma I.arge cell carcinoma
M
Both hemithordces
Adenocarcinoma
M
One hemithorax. livtr
Small cell carcinoma
TABLE 2 Tumour response .. ._
-_
-
Fxtent of di5ea\e
Sex
__
.
-.
'
_
..
I
-.
-
Patient
No.
A.V.
(1)
14 courses of therapy
Alive but new secondary developed whilst on therapy. Treated with radiotherapy. Therapy recently stopped at two years from commencement.
R.W.
(2)
I course
Sudden deterioration on therapy with acute massive pleural effusion leading to death.
C.H.
(3)
2 courses
Continued progression and death
G.B.
(4)
1 course
Sudden deterioration during therapy with massive pleural effusion and death.
D.F.
(5)
1 course
Continued deterioration and death.
J.C.
(6)
1 course
Massive pleural effusion. Deterioration and death after therapy
K.R.
(7)
1 course
Sudden deterioration during therapy with large pleural effusion leading to death.
S.H.
(8)
3 courses
Progression and death
W.N.
2 courses
Progression and death.
D.J.
(9) (10) (1 1)
4 courses I course
Progression and death.
M.L. A.H.
( 12)
1 course
Progression and death.
A.C.
(13)
3 courses
Progression and death.
J.T.
(14)
3 courses
Progression and death.
Course after heparinised chemotherapy ...
Sudden deterioration during therapy with acute and massive pleural effusion leading to death.
A m w r
1979
HEPAKINIZEI) CHIMOTIIERAPY I S CANC'ER
___
.~
seconds. This corresponds to a whole blood clotting time of three times normal as recommended by Elias ~t n/.3 Most patients required of the order of 1500 units to 2000 units hourly to maintain this level of anticoagulation. Chemotherapeutic agents given were as follows: cyclophosphamide 300 mgni!day on l h y b I and 5; 5-iluorouracil 7 . 5 mgm;kg!day on Days 1, 2, 3 , 4, 5; vincristine 0,015 mgm kg:day on Days 2. 5: methotrexate 0.25 mgm,kg'day on Days 1, 4. The drugs were given as a single intravenous bolus and a course was given on five days in every five weeks until either eleai- progression of disease o r death occurred. Daily PTTK and complete blood pictures were carried out and patients were not anticoagtilatcd in between courses of therapy.
Results
All patients tolerated thc chemotherapeutic regimen well and although four patients died during their first course of therapy. the deaths were not considered to be due to the chemotherapeutic agents, and apart from nausea, vomiting and alopecia there were no other drug-related side effects. The only objective evidence of tumour response was in patient number 10 who had a markedly elevated serum calcium associated with bony secondaries. The calcium fell to normal levels following the third course of therapy, but there was no overall benefit to the patient who died six weeks later following a fourth course of therapy. One patient remains alive after 14 courses of therapy. The patient had an adenocarcinoma of the left lung treated with radiotherapy and was started on heparinised chemotherapy when he developed a coin lesion in the opposite lung. There was no increase in size of this lesion during the first five courses of therapy, but then rapid growth became evident. The right lung lesion was then irradiated and the patient continued on heparinised chemotherapy for a period of t u o years. There has been no further evidence of tumour progression although the patient suffers from severe shortness of breath on mild exertion associated with radiation changes in his lungs. Therapy has now been stopped. No other patient showed any evidence of tumour regression or benefit from the heparinised chcmotherapy. Six patients were noted to have small pleural effusions prior to the commencement of therapy and in five of these patients the pleural effusions increased dramatically during therapy neces-
383
sitating pleural aspirations in all five. Only one of the five patients survived their first course of therapy and that patient died before a second course was begun. In the other four patients, one died three days after starting heparin and before chemotherapy was begun. one died five days after starting heparin and three days after chemotherapy was begun, and the remaining patient died seven days after starting heparin and five days after starting chemotherapy. All four patients became acutely short of breath with their effusions, all four had pleural aspirations (with 800 ml, 1200 ml, 1400 ml, 1450 ml being aspirated) and all four had large effusions still present at autopsy. The pleural effusions were blood stained in three out of the four patients, but in no patient was the effusion frankly bloody. Discussion
In their paper reporting on treatment for inoperable lung cancer Elias et crl. discuss the theoretical reasons for using heparin in association with chemotherapeutic agent^.^ Basically it was believed that fibrin forms an essential matrix for the tuniour and also prevents chemotherapeutic agents from penetrating the tumour. By anticoagulating the patient and preventing fibrin formation natural fibrinolysis can work unopposed and thus remove the fibrin matrix barrier. Although theirs was not a randomised study, they found no tumour regression in 14 patients treated with multiple chemotherapy alone and greater than 50:/(, tumour regression in seven patients out of 14 treated with heparin as well as chemotherapy. They reported no complications as a result of the heparin therapy. As a previous report using the regimen used in our study had shown a partial response in six out of 14 patients with bronchial cancer5, we were disappointed in our results where only one patient possibly benefited by this method of treatment. Dosages used in our regimen differed from that of Elias et al. in that we did not use 6thioguaninc and the course of therapy was used in a five-week cycle instead of a two-week cycle. One or both of these factors may have been responsible for our poorer results. Six patients had small pleural effusions at
the commencement of heparinisation and five patients developed massive increases in their effusions. So much so, in fact, that four patients died and the pleural effusions were thought to be the main precipitating factor in the deterioration which led to their deaths. The rclationship between the heparin and the pleural effusions may have been coincidental although the timing led us to consider that the heparin may have been causative. The mechanism is speculative although possibly a small fibrin rich effusion was converted by unopposed fibrinolysis to a more diffusable form. The numbers involved in this report are small and firm conclusions cannot be drawn. However, it is obvious that heparinisation is not going to convert any doubtfully efficacious chemothera-
peutic regimen into an effective treatment of disseminated lung cancer. And further, our experience indicates that heparinisation of patients with a malignant pleural effusion should be undertaken with great caution, and the patient should be observed closely for the development of a rapid increase in pleural effusion.
References I Sk.L.&wnY,0 S (1974): The rule of chemotherapy in the trcatmenl of lung cancer. Senwiors I?: 0 1 1 c o i o ~I ,i ~259 272. 2. LAN;, A. €1.. BI.RRY, K J , NIWHAV. C K.and 1 ' 1 ~ 0 ,J. (1975). 'Treatment of inoperable carcinoma of' the bronchus, [*mrrl 2, 1161~1164. 3. FLIAS. Cr. E . Sin,~l.n. S. K and MINK, 1. B (1975). Heparin and Chemotherapy in the manapcment of inoperable lung carcinoma. ('unwr 36, 129 136 4. J A M I ~ S O
