The treatment of malignant effusions with radioactive colloidal gold (AU198)

THE TREATMENT OF MALIGNANT RADIOACTIVE COLLOIDAL GOLD A Review of Sixty-Six

EFFUSIONS ( AUXg8)

WITH

Cases

S. H. SEAL, M.D., S. CROSIGNANI, M.D., G. VALVASSORI, M.D., J. J. NICKSON, M.D., AND D. AGOSTINO, V.M.D., NEW YORK, N. Y. (From Memorial Center for Cancer and Allied Research, and Cornell University Medical College,

Diseases, Sloan-Kettering New York)

Znstitute

for

Cancer

its introduction by Sheppard and Hahn in 1947, radioactive colloidal SINCE gold has been administered clinically as a therapeu.tic agent in various ways: intravenous injection in patients with lymphoma and chronic leukemia14vI61** ; direct injection into the tumor site in patients with inoperable tumors4 ; instillation directly into the bronchi in patient,s with bronchogenic carcinoma6 ; and, most frequently, intracavitary administration in patients with malignant pleural and peritoneal effusions.*y 3, *pI.19‘*I Is, 17-23, 26y32s3* The radiation characteristics of Auxs* make the use of this colloid appropriate for intracavitary therapy. Its 2.7 day half life provides a time period long enough for clinical purposes, yet short enough to avoid the possible damaging effects. Its decay products, which consist of -moderately energetic beta particles of 0.98 Mev and a soft gamma ray of 0.41 :Mev, allow for a uniform dose to the first few millimeters of the exposed serosal surface. Auls8 is prepared as a suspension of colloidal particles from 0.001 to 0.003 rnp in diameter. The size of the gold particles makes their absorption by the lymphatic and vascular systems negligible, and hence they remain in the cavity into which they are introduced. Miillerz3 first reported the use of radioactive colloiclal gold in the treatment of 8 patients with ascites due to peritoneal carcinomatosis. The resultant inhibition of fluid formation in these patients encouraged other groupsI* 2, 3, 18919923,269 28 to undertake this form of treatment. Their reports, which show favorable results in 30 to 40 per cent of the patients irradiated, confirmed the effectiveness of radioactive gold in slowing or stopping the formation of fluid in malignant effusions. Although the way in which radioactive gold acts to prevent fluid accumulation is not yet completely understood, several hypotheses have been offered: direct effect on the cancer cells, with elimination of the free cancer cell from t,he effusioP* **sI3 ; direct action on tumor seedlings present on the serosal

1028

SEAL ET AL.

Am. J. Obst.

& Gym. M.ay, 1958

surface8 ; and indirect action resulting in submesothelial fibrosis and obliteration of the blood vessels supplying the serous lining of the cavity.’ The purpose of this paper is to present the results of 4 years’ experience with the intracavitary administration of radioactive colloidal gold at the Memorial Center for Cancer and Allied Diseases.

Materials and Methods Therapeutic dosages of Auls8 were administered to 111 patients with malignant growths involving the pleural and peritoneal cavities. Treatment was administered to patients whose most important symptoms were due to fluid in the peritoneal and/or pleural cavities and who required frequent taps. All of the patients had effusions which were proved malignant by either cell block or biopsy at the time of exploration. Fifty-nine of the patients received intrapleural Aulg8 and 52 received intraperitoneal Aulg8. Sixteen patients in each group were lost to follow-up. Four patients in each group survived less than one month after treatment. This was considered too short a time for adequate evaluation of results and therefore these patients have been excluded from the study. Five patients treated prophylactically with the instillation of AulD8 to prevent the growth of spilled malignant cells have also been excluded. The remaining 66 cases are presented in this review. Patients with ascites received doses varying from 150 to 225 me. in the first injection, with an average of 175 me. Patients who received pleural therapy were given a single dose ranging from 75 to 110 me., with an average of 85 mc. The radiogold was diluted with a volume of 200 to 250 C.C. of isotonic saline solution to ensure a proper distribution of the radioactive material in the cavity and was injected after the method of Rose and associatesZ6 The size of the dose was adjusted to the individual patient, with the initial dose never greater than 110 mc. for pleural therapy and 225 me. for peritoneal therapy. The highest doses were administered in the abdominal reinjections given to 3 patients: (1) 375 me. in three divided injections ; (2) 530 me. in four injections; (3) 675 me. in five injections. These doses were administered over a period of 28 months and were tolerated well by all patients. To obtain an adequate distribution of the material, some movement of the patient from time to time is recommended during the first hour after the injection. At intervals after administration, a routine survey of the abdominal wall was performed, with the use of a shielded Geiger-Mueller counter. Usually an autoradiograph, a chart of the area, was drawn to detect any “hot” area due to the accumulation of the radiogold in a localized region of the cavity. This chart gave satisfactory quantitative data from the clinical point of view. In other instances, qualitative data on the distribution of the colloid were analyzed. Utilizing these methods, local overirradiation and subsequent necrosis due to the radiogold injection were prevented.

Results The palliative results in this study were analyzed in terms of the length of time required for the fluid to reaccumulate in the cavities. We used the time period most frequently used by previous investigators in order to facilitate comparison of results. “Good palliation” was achieved when no taps were required for a period of at least 2 months after treatment (we include in this group the patients who received complementary taps 15 to 20 days after

MALIGNANT

g)du;,‘,”

EFFUSIONS

the gold instillation when of rest). “ Fair palliation period of one to 2 months when a tap was required accumulated in less than 2 The survival period of The radioactive injection, survival time.

TREATED

WITH

RADIOACTIVE

3029

GOLD

the last tap was followed by a8period of 2 months ” was achieved when taps were required within a after treatment. “No palliation” was recorded less than one month after treatment and fluid remonths. the treated patients is reported in Tables T and II. however, seems to have no detectable effect on the

TABLE I. EFFUSION

RESULTS OF TREATMENT AND SURVIVAL IN 34 CASES OF MALIONA.NT PLEURAL TREATED WITH INTRAPLEURAL INJWTION OF RADIOACTIVE COLLOIDAL GOLD --SURVIVAL(MONTHS) RESULTS* NO.OF 1 6-12 ( >lsTUMOR ORIGIN ( NONE 1 1-3 1 3-6 I CASES I GOOD 1 FAIR

Lung

Ovary Breast Lymphoma Rectum Pleural mesothelioma Corpus uteri Undeterminable Total % 'Good: Fair: None: TABLE

4 1 : 1 10034

9 6 2 2

5

2

1

1

1

1

1 1 1 1 23 67.6

5 2 2 2 1

7 2

3 2 ;

1 1

1 1 1 20.6 7

11.8 4

35.3 12 __-

11 32.4

23.5 8

___I-

i.8

no taps required for a period of at least 2 months. no taps required for a period of from 1 to 2 months. taps required within a period of less than 1 month.

II. RESULTS TREATED WITH

TUMORORIGIN Ovary Rectum Colon Stomach Breast Liposarcoma Corpus uteri Undeterminable Pancreas Total %

16 6 4

OF TREATMENT AND SURVIVAL IN 32 CASES OE MALIQNANT ASCITES INTRAPERITONEAL INJECTION OF RADIOACTIVE COLLOIDAL GOLD A RESULTS SURVIVAL(I.IONTRS) __-1 6-12 1 >12 ) 3-6 I CASES I GOOD ( FAIR 1 NONE / 1-3 20 11 5 4 8 7 l4 3 3 2 1 3

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100

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19

14 43.8

9 28.1

5 15.6

If.5

Of the 34 patients treated intrapleurally, 28 received treatment once on one side. Three patients received treatment twice on one side, with an interval of 3 to 41/s months between doses. The total dose for these patients was 110 to 260 mc. One patient was treated three times on the same side with intervals of 11/s months between the first and second instil.lation, and 8 months between the second and the third instillation. The total dose was 220 me. Generally, the response after the second instillation was less than the response following the first. Four patients received concurrent intrapleural and intraperitoneal treatment. In this group good palliation was obtained at both sites in 2 patients (Cases 13 and 86). The remaining 2 patients (Cases 81 and 75) both died too soon to be included in this survey. Three patients received methyl&is (/3-chloroethyl)-amine (HN2) intravenously in doses ranging from 12 to 28 mg., and 2 received HN2 directly in

the thoracic cavity. Two had triethylene melamine (TEM) injected into the pleural cavity 2 to 21/z months after the gold instillation. During the same period of time, 7 patients received roentgen-ray therapy to the chest in closes ranging from 2,000 to 4,000 r tumor dose and gold instillation in the pleural cavity. Good results were achieved in controlling the fluid. Many patients received combined therapy, such as gold instillation and radiotherapy or radiotherapy and chemotherapy. In these situations evaluation of results was difficult, since each type of therapy may have contributed.

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MALIGNANT

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EFFUSIONS

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WITH

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of paracentesis ascites.

before

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SEAL

ET AL.

Am. J. Obst. & Gynec. May, 1958

12 months. One patient who survived 13 months (Case 34) had received 4,000 P tumor dose to the hemithorax 5 months after gold instillation in the same cavity. The longest survival period (46 months) was noted in the patient with epidermoid carcinoma of the lung (Case 13). This patient was treated three times with gold instillation and once with roentgen-ray therapy to the hemithorax (2,000 r tumor dose). Sex, age, primary site of the instillation, and type of therapy administered to each patient are summarized in Fig. 1. Palliative results and survival data are set forth in Table I. Of the 32 patients treated intraperitoneally, 19 received only one injection. Three patients received more than one injection. Three patients received gold instillation and roentgen-ray therapy (2,500 to 4,000 r tumor dose) concurrently. In one patient (Case 73) the peritoneal cavity was treated with gold and the pleural cavity with HN2, the total dosage being 20 mg. Both forms of therapy resulted in effective palliation. Sixty-two per cent of the patients treated intraperitoneally had ovarian tumors, and 21 per cent had tumors of the large bowel (see Table II). Good palliation was achieved in 19 of these patients, fair palliation in 7, and no palliation in 6. The survival period of these patients ranged from one to 29 months, with an average survival time of 5.8 months. Forty-four per cent survived from one to 6 months, 16 per cent survived from 6 to 12 months and 13 per cent survived more than 12 months. One patient (Case 22) with papillary adenocarcinema of the ovary survived 27 months after the first gold injection. Between the second and the third administration he received abdominal roentgen-ray therapy (3,000 r tumor dose). This treatment was administered four times with good palliation indicated after gold instillation. Another patient (Case 67) with ovarian adenocarcinoma had required paracentesis almost every 2 weeks before the administration of gold. She survived 4 years after treatment without requiring further paracentesis. This exceptional case was not included in the calculation of the median survival. The data for patients who received peritoneal therapy are reported in Fig. 2. The results and survival data are reported in Table II. No complications due to surgical trauma, local action of the radioactive gold, or infection were observed in any of the patients included in the survey. The usual side effects of radiation therapy in the form of slight nausea and vomiting during the first 24 to 48 hours after the gold instillation were present in most of the patients. Blood studies performed before and after the treatment did not show any serious bone marrow depression. Permission for autopsy was obtained in approximately 23 per cent of all the 111 cases. The most frequent findings in the treated cavities were marked homogeneous thickening of the peritoneal, pleural, and visceral surface due to an increase in hyaline connective tissue. The serosal membranes were often opacified, gray or bluish purple in color, and roughened. The thickening varied widely, without any correlation between the amount of gold administered and the degree of thickness. In 2 patients several islands of tumor cells surrounded by marked fibrosis were found included in the serous membranes, with a complete walling off of the tumor tissue. In several patients the lymph nodes adjacent to the treated areas were found to contain phagocytes with abundant black pigmented material presumed to be gold. The normal tissues surrounding the treated regions did not indicate any alterations due to the gold. In some of the patients treated with 150 me. of AuXQsin the abdomen, areas of the musculature of the bowel had vacuolization of the cytoplasm, focal atypica, areas of necrosis, and other changes which probably occurred

gLd;;;r7;

MALIGNANT

EFFUSION8

TREATED

WITH

RADIOACTIVE

GOLD

1 ()$j

as reaction effects. In the same patients aggregates of gold were seen in the macrophages of the liver and spleen, with foaal areas o:Enecrosis and disruption of the liver cords. No abnormalities were found iu the bone marrow of any of the patients at the postmortem examination.

1. In our survey 66 patients were observed. Good palliation was achieved in 63.6 per cent of the patients, moderate palliation was achieved in 21.2 per cent, and no palliation was achieved in 15.1 per cent (Figs. 1 and 2). 2. Approximately 70 per cent of the patients experienced relief from the subjective symptoms. 3. There is no correlation between survival time and administration of AlP”.

We express appreciation to H. N. Bane, M. H. Friedman, for helpful suggestions and criticisms.

J. Belier,

and I. Leskowitz

References 1. Anderson, G. A., Root, S. W., and Kniseley, R. M.: Cancer 6: 294, 1953. 2. Andrews, G. A., Root, S. W., Kerman, H. D., and Bigelow, R. It.: Ann. Surg. 137: 375, 1953. 3. Andrews, G. A., Root, S. W., Kniseley, R. M., and Kerman, R. R.: Radiology 61: 922, 1953. 4. Berg, H. F., and Cristophensen, W. H.: Am. J. Burg. 22: 172, 1956. 5. Berg, II.: A. M. A. Arch. Surg. 67: 228, 1953. Berg, H. F., Cristophensen, W. H., and Bryant, J. R.: J. Thoraeic Burg. 29: 497, 1953. ;I Botsford, T. W., Weeler, H. B., Newton, R. A., and Jaques, W. I).: J. A. M. A. 151: 788, 1953. 8. Chamberlain, R. H., Klingermith, P., and Hale, J.: Chicago Abbott Laboratories, Periodical 25: 1953. 9. Cowan, J., Cron, R. S., Gordon, F., and Karioris, F. G.: Surg., Gynea. & Obst. 98: 721, 1954. Cowan, J.: AM. J. OBST. & GYNEC. 69: 312, 1955. :: Goldie, H., and Hahn, P. F.: Proc. Sot. Exper. Biol. & Med. 74: 638, 1950. 12: Goldie, H. : Proc. Sot. Exper. Biol. & Med. 76: 477, 1952. 13. Goldie, -_ --H.: Proc. Soe. Exper. Biol. & Med. 80: 327, 1952. 14. Hahn, P. F., and Charoters, E. L.: Nucleonics 6: 54, 1950. 15. Hahn, P. F.: Am. J. Roentgenol. 75: 1139, 1956. 16. Haigler, M. L., and Williams, G. Z.: Cancer Research 2: 253, 1951. 17. Kent, E. M., and Moses, C.: J. Thoracic Surg. 22: 503, 1951. 18. King, E. R.: J. Am. Geriatrics Sot. 4: 131, 1956. 19. Kligerman, M. M., and Habif, D. V.: Am. J. Roentgenol. 74: 651, 1955. 20. Kniseley, R. M., and Andrews, G. A.: Cancer 6: 303, 1953. 21. Maleom, Y.: M. Clin. North America 36: 1133, 1954. 22. Mellgreen, J.: Acta path. scandinav. 84: 393, 1954. 23. Miiller, J. J.: Bull. schweiz. Akad. Med. Wissensoh. 5: 484, 1949. 24. Pluygers, E.: Inst. Beige de radiol. 33: 156, 1950. 25. Rominger, C. J.: Ann. Surg. 86: 574, 1954. 26. Sohich, Rose, R.A.,G., and Osborne, B.: 64:New J. Med. 247: 663, 1952. 27. Booth, M.R.:P., and New Stevens, York J. W. Med. 21, England 1954. 28. 29. Seaman, Schoolman,W. H.R., M., Sherman, and Schwartz, A. I., andSteven Bonebrake, 0.: J. M.: A. M.J. A. A. 160: 116.A. 163:1956. 630, 1953. 461, 31. 30. Sherman, Simon, A.: A. J. I., Mt. Nolan,SinaiJ. F., Hosp. and 21: Allen, 273,W.1953. M.: Am. J. Roentgcnol. 64: 75, 1951. 32. Smithers, D. W.: Acta radiol. 33. Stapleton, J. E.: Nucleonics II: 34. Storassly, J. P.: Surg., Gynec. 35. Walton, R. N.: Brit. M. Bull.

36: 48, 1951. 60, 1953. & Obst. 94: 707, 1953. 8: 156, 1953.