The therapy of sarcomas by isolation perfusion

The

Therapy

of Sarcomas Perfusion

by Isolation

DONALD B. ROCHLIN, M.D., Los Angeles,

California

From tbe Department of Surgery, University of Calijornia, Los Angeles, Calijornia. Tbis work was supported by a grant from the United States Public Healtb Service (CY-5049), Washington, D. C.

tions were turned toward the combined these agents during isoIation perfusion.

SOLATION perfusion is primariIy designed for the therapy of IocaIized maIignant disease that is, for one of several reasons, beyond the scope of surgical resection. The use of the procedure for the therapy of sarcomas, therefore, has been a natura1 evolution. Sarcomas as a group have a great tendency for local recurrence after primary surgica1 excision and, atso, for hematogenous metastasis rather than lymphatic spread. These tumors may produce severe disabIing IocaI symptoms even though no evidence of metastatic disease is present. Isolation perfusion may, therefore, be indicated either as an attempted curative procedure or as palliative treatment to decrease the size of the buIky Iesions and the symptoms caused by Iarge tumor masses. Many different chemotherapeutic agents have been used in an attempt to cause regression of these tumors, but the inherent resistance of these Iesions to perfusion as we11 as rapid recurrence of disease foIIowing initial response, has limited their usage. For these reasons, our interest has been focused on sarcomas, and an attempt has been made to develop standard therapeutic regimens for the treatment of these tumors by isotation perfusion. The potentiating effect of actinomycin D upon ionizing irradiation [I] stimuIated our interest into the possibilities of potentiating the effect of a radiomimetic alkyIating agent in a similar fashion. Our earher experiences had shown some Iimited effectiveness with actinomycin D and L-sarcoIysin when these agents were administered systemicaIly to treat wideIy metastasized sarcomas. Thus, our investiga-

Laboratory studies were performed with the hind Iimb of a mongrel dog as the standard preparation. A tourniquet was placed high on the thigh of the animal, and the common femora1 artery and vein were used for pIacement of catheters during the operative procedure. CoIIateraI vessels were divided in the groin area. Animals were perfused at constant temperature IeveIs and with complete oxygen saturation of hemoglobin. The rate of perfusion was kept constant, as measured by cubic centimeters per minute per kilogram of body weight. A number of combinations of aIkyIating agents and actinomycin D were studied, and it was found that L-sarcoIysin could be used in combination in a dosage cIose to that which wouId have been administered alone. TabIe I is the summary of the data on the experimental

I

use of

EXPERIMENTAL TECHNICS

TABLE EXPERIMENTAL DOSAGE

OF

MYCIN

I_-SARCOLYSIN D

OF

NECESSARY

SLOUGH OF

I

THE

(PAM)

ADMINISTERED

PERFUSION, SKIN

I

DETERMINATION

IN

THE

A

DOG

AND

COMBINED ACTINO-

BY

ISOLATION

TO

PRODUCE

HIND

I

LIMB

I

___ 40 40 40 40 40 $0

1.0 I.2

1.3 1.4 I.5 I.5 615

American

Journal

of Surgery,

0 0

2 2

Volume

roe.

May

1963

Rochlin TABLE II Dos.4fx 0~ L-SARCOLYSIN (PAM) D

USED

CLINICALLY

IN

OF

AND

ISOLATION

PERFUSION

SARCOMAS

L-SarcoIysin

Type of Operative Procedure

vein are cannuIated. The cannuIas are then passed proximaIIy for a short distance (I to 1.5 inches) so that the coIIatera1 ffaw around the scapuIa and axiIIary areas are not occIuded. The second Steinmann pin is inserted into the cIavica1 just dista1 to the sternocIavicuIar junction. A tourniquet, made of I inch rubber tubing, is drawn taut, and the scapuIa is elevated from the posterior surface of the chest waI1 with isoIation of the entire shoulder girdIe and axiIIa. A mid-line incision is Pelvic Perfusion. made from the symphysis pubis to the xiphoid process. The aorta and vena cava are mobilized distaIIy from the origins of the renaI artery and vein, incIuding the externa1 iIiac artery and vein to the point of origin of the inferior epigastric vesseIs. AI1 of the Iumbar veins are cIamped and divided. The lumbar, inferior mesenteric, superior hemorrhoida middIe saand externa1 iIiac epigastric cra1, inferior arteries are occluded. The externa1 iIiac, testicuIar and superior femora1 veins are aIso occIuded. Pneumatic tourniquets are applied high on both thighs. ProximaIIy, the aorta and vena cava are occIuded just dista1 to the renaI vesseIs, and both are cannuIated I to 2 inches proxima1 to their bifurcations. An incision is made External Carotid Artery. overlying the thyroid cartiIage, curving from one mastoid process to the other. The anterior and externa1 juguIar veins and the several cervica1 branches of the coIIatera1 veins emptying into the interna juguIar are divided. The externa1 carotid artery and common facia1 veins are cannuIated for the perfusion. AI1 patients operated upon underwent tota body hypothermia with the body temperature Iowered to 30 to 32’~. Following cannuIation of the vesseIs and isoIation of the area, the temperature of the perfused part was elevated by means of perfusion with bIood warmed to approximateIy 38”~. Papaverine@* ( ISO to 250 mg.) was administered at the start of the isoIation perfusions, and in a11 cases, the chemotherapeutic agents were injected in four equaIIy divided dosages at approximateIy two minute intervals. At the completion of the isolation perfusion, the perfused area was washed cIear of perfusate with two bottIes of bIood uncontaminated by chemotherapeutic agents. Arterial and venous pressure measure-

ACTINOMYCIN

(PAW (mg. per Kg.)

Forequarter perfusion, ExternaI carotid perfusion. . Hindquarter perfusior Pelvic perfusion.

I.2

0.8 1.5 I.7

Actinomycin D (mg.per Kg.)

40 40 50 50

I

animaIs showing that a dosage of 1.5 mg. per Kg. of body weight and 50 pg. per Kg. of body weight of actinomycin D was toIerated in the majority of the animaIs, but did produce some skin necrosis in two of the dogs tested. The cIinica1 appIication of this dosage regimen is noted in TabIe II. OPERATIVE

TECHNICS

The operaHindquarter Isolation Perfusion. tive incision is made either through a retroperitonea1 or transabdomina1 approach. The deep circumflex iliac vesseIs and the inferior epigastric vesseIs are Iigated, and the hypogastric arteries are occIuded during the course of the perfusion. The remainder of the arteria1 branches coming from the external iIiac and femoraI vesseIs are aIlowed to remain open. The externa1 iIiac artery and vein are cannuIated just beyond the bifurcation of the common iIiac artery. Prior to starting isoIation perfusion, a Iength of rubber tubing I inch in diameter is drawn taut as a tourniquet. The tourniquet is appIied so it overIies the iIiac crest where it is heId in pIace by a Steinmann pin previousIy inserted into the highest point of the iIiac crest. The tourniquet then runs posteriorIy and medially through the gIutea1 crease and over the groin area. If an excision of the inguina1 nodes is to be performed, the isoIation perfusion is done first and is then foIlowed by the radica1 groin dissection. A Steinman Forequarter Isolation Perfusion. pin is inserted at the tip of the scapuIa and passed upward posteriorly to it. The scapuIa is pierced in its central portion and the pin is fixed at the base of the scapuIar spine. An infracIavicuIar incision is made so that the most dista1 part of the subcIavian artery and

* Papaverine,@ Indiana. 616

Eli

Lilly

Company,

Indianapotis,

Therapy

of Sarcomas

by IsoIation

TABLE III RESPONSE OF SARCOMAS

THE

VARIOUS

UNDERGOING

CELLULAR ISOLATION

-

Type of Tumor

Positive

TYPES

Perfusion

TABLE IV LENGTH OF REMISSION IN PATIENTS

OF

PERFUSION

FOLLOWING

POSITIVE

PERFUSION

1Negative

rota1

I

4 IO 8 4 IO

RESPONSE

L-SARCOLYSIN ACTINOMYCIN

WITH TO

SARCOMAS

ISOLATION

(PAM)

AND

D

Months Chondrosarcoma. Osteogenic sarcoma Fibrosarcoma........... Liposarcoma. Rhabdomyosarcoma. Kaposis sarcoma. Leiomyosarcoma. SympathicobIastoma. Lymphosarcoma. Neurofibrosarcoma Mesothelioma.

5 3 I 2 I I 0 0 I

I TotaI Positive

I

I O

Type of Tumor 4to 6

Izto 18

I8to 24

24+

____

3 3 I I 2 I

Chrondrosarcomas. Osteogenicsarcoma Fibrosarcoma.. Lipsarcoma............ Rhabdomyosarcoma. Kaposis sarcoma.. Leiomyosarcoma. SympathicobIastoma. Lymphosarcoma. Neurofibrosarcoma. Mesothelioma. ..

47 Response..

6to I2

32

ments of the perfused area were taken in the early procedures in the study, but when it was found that these measurements varied as the rate of arteria1 Aow and couId be kept Iower than the systemic arteria1 and venous pressures by maintaining a Iower than normal ffow rate, the pressure measurements were discontinued. A11 patients underwent one hour of isoIation perfusion.

(I)

....

(I)

1 (I) 2

(I)

I (I)

(I)

I

(I)

I (I)

(I)

. ,

(I)

I (1) 2 (1) I I

(I)

1 (2) (1) (1)

I

(1)

(I)

Note: The numbers in parentheses remission from disease.

are patients

stiI1 in

of narcotics for some patients. Those patients, however, have not been cIassified as having positive responses since the criteria of objective signs of remission were not fuIfiIIed. TabIe IV shows the Iength of remission of patients cIassified as having a positive response as of May I, 1962. Those patients in parentheses remain free in an arrested state and in remission from their disease at the time of this rating. Those not in parentheses are recorded in the tabIe as the Iength of remission demonstrated prior to recurrence of their disease process. At the present time, two additiona groups of patients are being studied. One group of patients in whom marked regression of tumor occurred and onIy smaI1 remnants of disease remained, underwent IocaI resection of this tissue at the peak of the regression period foIIowing perfusion. This is generaIIy estimated to occur six weeks after therapy. A second groups of patients are being studied in whom the IocaI disease has been surgicaIIy excised, and in whom the isoIation perfusion is being performed on a prophyIactic, experimental basis in order to evaIuate the effect of the therapy as an adjuvant to surgica1 excision. It is to be emphasized that this Iatter group is an experimenta series and it wiI1 be severa

RESULTS

A tota of forty-seven patients with pathoIogicaIIy identified sarcomas underwent isoIation perfusion with the combined regimen of L-sarcoIysin (PAM) and actinomycin D. The response of tumors was rated as either positive or negative by means of the folIowing criteria: (I) a reduction in the size of the tumor of 50 per cent or more, (2) a remission continuing for a minimum of four months, and (3) subjective improvement. TabIe III enumerates the types of tumors and their response to this therapy. Among those of which a sufficient number were perfused to evaIuate the therapy, the most responsive type of sarcoma was the rhabdomyosarcoma, whiIe the most resistant were the osteogenic sarcomas. However, many patients who were cIassifIed as having a negative response to therapy experienced a marked subjective improvement in terms of reduction of pain, in spite of the fact that objective signs of remission did not occur. The decrease of pain in the perfused area aIIowed the discontinuation 617

Rochlin years before any evaIuation procedure can be made.

of this

type

of

SUMMARY

The technic for isoIation perfusion of sarcomas as done at the University of California Medical Center in Los Angeles is described. A tota of forty-seven patients have undergone isolation perfusion with the combination of L-sarcolysin (PAM) and actinomycin D as the chemotherapeutic agents; in thirty-two of these patients, positive responses have been obtained. Of this group of patients, four now survive two years or more folIowing perfusion with no evidence of recurrent disease at the present time. New experimenta studies are in progress to

evaIuate the effect of isoIation perfusion as an adjunct to surgica1 excision, and to evaIuate the effectiveness of IocaI surgica1 resection of any tumor masses remaining after a positive response to this therapy. I acknowIedge with the kind cooperation of Elmer Alpert, M.D., Merck Sharp & Dohme Research Laboratories for suppIying the actinomycin D and DonaId S. SearIe, PH.D., M.D., Burroughs WeIIcome & Co., Inc. for suppIying the MelphaIan used in the study. Acknowledgment.

thanks

REFERENCE I.

618

D’ANGIO, C. J., FAKBEK, S. and MADDOCK, C. L. Potentiation of x-ray effects by actinomycin D. Radiology, 73: 175, 1959.