CHEMOTHERAPY OF INVASIVE THYMOMA

B A K R Y BOSTON, AID"

Despite conventional therapy, including surgery and radiation, 5-year survival for invasive thymoma remains poor. Chemotherapeutic agents, including cis- diamminedichloroplatinum, prednisone, adriamycin and nitrogen mustard- vincristine-vinblastine-procarbazine, and bleomycin-adriamycin-CCNU-vinrris- tine have produced short-term remissions. In view of the small number of cases seen in any one institution, a cooperative study to evaluate chemotherapeutic efficacy in malignant thymoma would seem worthwhile.

Cancer 38:40-52, 1976.

NVASIVE 'I'HYMOWA IS A MALIGNANT DISEASE I because of its cont iguous spread, p leura l seeding and metastasis wi th dysfunct ion of involved structures, and resul tant poor 5-year survival. C u r r e n t therapy has n o t significantly modified t h e poor prognosis. 17, 19,34 We have recently seen t w o pa t ien ts whose disease pro- gressed despi te surgical a n d i r rad ia t ion ther- a p y and , therefore, who were given trials of chemotherapy. T h i s paper is a review of t h e l i t e ra ture concern ing chemotherapy of in- vasive thymoma w i t h t h e addi t ion of two n e w cases.

CASE REPORTS

Case 1 K.hl. was a 17-year-old asymptomatic woman

who in August 1969 showed a mediastinal mass on chest x-ray. At surgery, an unresectable epithe- lial tliymoma was present. Radiation therapy (3675 rads over 28 days) reduced the mass size. In April 1970, a soft tissue mass on the right posterolateral thorax developed and radiation (3450 rads over 12 days) decreased its size. Exten- sion of the primary to the left mediastirium and lung was noted i n J d y 1970. Hepatomegaly with

From the Department of Internal Medicine, Section of Medical Oncology, Yale University Scllool of Medi- cine, New Haven, Connecticut.

Supported by Grant Nos. C.4 05138 atld C.4 08341 from IJSPHS.

* Postdoctoral Fellow. Address for reprints: Barry Boston, MD, Rlcdical

Oricology Section, Veterans Administration Hospital, 1030 Jefferson Avenue, Memphis, T N 38104.

The author acknowledges Drs. John C. Marsh and Roland T. Skeel for permission to describe the patients. and Drs. David Berd, Harvey Kaetz, M. S. Mitchell and J. K. Bertiiio and Ms. Mary Jessup lor their as- sistance in prepaiation of the maiiuscript.

Reccivcd for puh1ic;ttion Septetnl)c~r 3, 1975.

normal liver function studies was present. Chlor- ambucil 9 mg daily was given from August 5 through September 16 producing leucopenia; however, left supraclavicular and neck masses ap- peared. I n October, nitrogen mustard at 0.3 mg/ kg and vincristine, followed by procarbazine and vinblastine,25 were begun. Reduction of the supra- clavicular and neck masses was observed. A second cycle produced continued decrease in the neck mass and a reduction of left lung mass. De- spite initiation of a third cycle, increase in nodal and pulmonary mass size and a right breast mass were noted in February 1971. Radiologic studies done in April because of bilateral lower extremity edema and left lower lobe infiltrate revealed ex- trinsic compression of the inferior vena cava, stomach, and small bowel secondary to intra- abdominal lymphadenopathy and Iiepatomegaly. O n April 28, adriamycin, 0.4 mg/kg q 8 hours for six doses, was begun, resulting in disappearance of the breast mass and diminution in supraclavic- ular nodal size and the inferior vena cava syn- drome. I n June, the breast mass and vena c a d syndrome recurred and a liver scan revealed numerous filling defects. Adriamycin, 0.18 mg/kg for six doses, was given but the patient died o n J u n e 17, 1971. Postmortem examination, limited to liver and lung biopsies, was nondiagnostic.

Case 2 D.L. was a 28-year-old women who was admitted

in June 1973 with superior vena caval syndrome arid right vocal cord paralysis. Chest x-ray revealed a mediastinal mass and operative biopsy was re- ported as mixed (lymphoepithelial) tliymoma. Radiation therapy (6400 rads over 6 weeks) to the mediastinum was given. I n December, 4800 rads over 3 weeks were delivered to a right Insilar pleural nodule. An intravenous pyelogram, done to investigate a BUN of 20, demonstrated a non- functioning left kidney and an enlarged right kidney. Diffuse, bilateral infiltration of the kid- i i ev~ by tliymoma was discovered upon laparotomy

49

50 CANCER JuZy 1976 Vol. 38

in March 1974. Nitrogen mustard and vincristine followed by procarbazine and vinblastineZ5 were begun. Transient but definite improvement in renal function occurred. Nitrogen mustard, as a single agent, was given in May without definite effect. Chlorambucil, 4 mg daily for 14 days, pro- duced no improvement. Pleural and pericardial effusions developed but fluid and pleural biopsy studies revealed no tumor. In July, bilateral renal radiation therapy (2100 rads over 16 days), fol- lowed by adriamycin 40 mg/mz, CCNU 50 mg/mz, vincristine 0.5 mg and, 1 day later, bleomycin 5 mg, was given. Serum creatinine decreased from 8.9 to 4.7 following a second cycle of chemother- apy. Pleural and pericardial effusion slowly re- curred and serum creatinine remained 5.1-5.9 mgJ 100 ml over the next 3 months with supportive uremic care and three further cycles of chemo- therapy. In November, despite removal of ef- fusions, severe dyspnea developed and death oc- curred on November 22 a t her home. Autopsy was not done.

DISCUSSION

T h e treatment of invasive thymoma cur- ren tly consists of combination surgery a n d

irradiation therapy.1*5,1$~34 The extensiveness of surgery varies from simple biopsy and confirmation of diagnosis t o excision of all nonvital structures involved by continuous spread of the t ~ m o r . ~ , 7 ~ 1 ~ ~ ~ 6 Radiation ther- apy usually involves 4000-6500 rads given to the mediastinum a n d lower neck.

Age, cell type a n d presenting symptomatol- ogy relate t o prognosis.4 Patients less than 25 years of age have an extremely poor prog- nosis, with a 2-year survival approaching 07&.59,73,13334 All thymomas included, epithe- lial predominant histology cases have a 4 1- 447, 5-year survival; mixed (lymphoepithelial) cases, 55560%; lymphocytic cases, 13-77y0; a n d spindle cell variety, 50-77'%.3,1s T h e rea- son for the wide variance in percentages with a cell type probably relates to the percentage ol patients in that type who had invasive thy- moma, i.e., the higher the percentage of in- vasive thymoma, the lower the percentage with a 5-year survival. Patients symptomatic o f the tumor mass have a 3.2-3.5-year mean survival a n d a n 0% 5-year s u r ~ i v a 1 . * ~ ~ ~ 6 ~ ~ ~ Overall survival for patients with invasive

TABLE 1. Cases in which Chemotherapy Was Utilized for Invasive Thymorna

Study . \~e-Sex Cell type Drug Dosage Responre

L V h i t a I ~ x ~ ~

R I ot tet20

32F epithelial

35M mixed

58F spindle 44F mixed

viiicristine 2 n x

chlorambucil 8 nix daily

cyclophosphamide 120 rng daily

.\CTH - prednisone 60 mg daily

chlor,intbicc.il 8 niq daily

steroids .-

. \CTH 2 5 ing qid for 10 days

nitrogen inustard __ Ohf F-59 (aI1alog of -

cyclophosphaniide) cis-dianiminedi- see text chloropla ti nu in vincristine and .-

vinblastine

Progression of lesions. Stopped after 7 mo. Progression of lesions. Stopped after 24 days. No change in lesions. Stopped after 6 days. No change in lesions. No change in rnediast-inal mass. Stopped after 2 mo. No change in lesions. Stopped after 1 mo. No change in mediastinal mass. Decrease in mass. Rapid regrowth on discontinuation. See text. Progressive deterioration. No response. Phase I trial.

Remission for 13 months. Phase I trial. See text. No response. Phase I trial.

17F epithelial chlorambucil 9 rng daily No response. M . V. P. \7. adriani yci n see text Partial remission for 1 month.

see text Partial remission for 3 months.

Phase I trial. See text-. 28F mixed M.V.P.V. see text Partial remission for 3 wk.

chlorarnbucil 4 nig daily No response. C.V. B . see text Partial remission for '7 wk. :Ilso received

radiation therapy. See text. -__.

No. 1 CHEMOTHERAPY OF INVASIVE THYMOMA - Boston 51

thymoma ranges from 10-28 months with a 23-507” 5-year s~ i rv iva l3~~”~7~l9~ .”~ and an 0% 10-year survival.27 The effect of myasthenia gravis on survival of patients with invasive tliymoma remains controversial.4,32

Chemotherapy as a mode of therapy has never been systematically evaluated. Table 1 presents 10 cases from the literature and our two cases, for which evaluation of chemother- apy is possible. Several reports in which chemotherapeutic agents were used are not included due to the absence of specification of the therapeutic drug(s) or tumor re-

T h e longest remission described is a 13- month remission using cis-diamminedichloro- platinum for 5 days repeated every 4 weeks. The dosages utilized were 4 mg/m2 for the first dose, 6 mg/m2 for the second, and 10 mg/mz for the third and fourth. Due to azo- temia, the dosage was decreased to 5 mg/mz lor the next six closes. Therapy was discon- tinued due to disease progression and azo- temia.

In one patient, adriamycin at .4 mg/kg every 8 hours for six doses, produced disap- pearance of a breast mass, shrinkage of a supraclavicular node, amelioration of an in- ferior vena caval syndrome, and an improved sense of well-being. Progression was noted 4 weeks later ancl a second, reduced (because of hepatomegaly) dosage of adriamycin pro- duced no therapeutic effect.

ACTH given at 25 mg four times per day for 10 days caused reduction in thymic size and a suggestion of pleural nodule shrinkage on serial chest x-rays. Progression occurred within 16 days after discontinuation of ACTH, but was again checked by a 10-day course of ACTH. Cortisone 200 mg daily was later used in this patient, with reduction in thymic size, but control of co-existent myas- thenia gravis became difficult.

~ ~ ~ o n ~ e . l , 2 , 7 , 9 , 1 1 , 1 2 , 1 3 , 1 4 , l ~ , 2 2 , 2 3

Nitrogen mustard, vincristine, vinblastine, and procarbazine were utilized in two of our patients. The first experienced progressive de- crea5e in neck mass over two courseS in wliich .3 mg/kg and 2 5 mg/kg of nitrogen mustard were used, respectively. However, the neck mass increased in siLe and a breast mass ap- peared during the tliird cycle. T h e second, with diffuse bilateral renal involvement, dem- onstrated a decrease in serum creatinine fol- lowing the initiation of mustard, vincristine, vinblastine, and procarbahe . During the first cycle, 3 weeks following the nitrogen mustard, the creatinine began to rise. A second dose of nitrogen mustard only slowed down the rate of elevation of serum creatinine. Following an unsuccessful trial ol chlorambucil, radia- tion therapy bilaterally to the renal areas and adriamycin, vincristine, CCNU and bleomycin were initiated. Adriamycin 50 mg, CCNU 80 mg, ancl vincristine .5 mg were given on Day 1 and bleomycin 8 mg was given on Day 2. This was repeated on Day 21. T h e creatinine ini- tially fell, but following the third cycle, rose again. Two more cycles of the adriamycin, vincristine, CCNU, and bleomycin produced no effect. The efficacy of the last four drugs is unevaluable, as the decrease in serum cie- atinine may have been due to the renal ir- radiation.

From the information presented, it is clear that no outstanding drugs are available, at least for advanced disease. Cis-diammine- dichloroplatinum, prednisone and adriamycin as single agents and combinations of nitrogen mustard, vincristine, velban, procarbazine and bleomycin, adriamycin, CCNU, and vincris- tine may have demonstrated responses of short duration. Nitrogen mustard as a single agent ha5 been advocated by some, but no data are yet available that permit an objective eval- uation.

REFERENCES

I . Batata, M. A., Martini, N., Huvos, A. C., Aquilar, R. I., and Beattie, E. J., Jr.: Thymomas-Clinicopatho- logic features, therapy and prognosis. Cancer 34:389.- 396, 1974.

2. Bergh, N. P., Rosengren, B., and Secman, T.: Treatment of tumours of the thymus. Scand. J. Thorac. Cardiovasc. Suig. 2:65-69, 1968.

3. Bernatz, P. E., Harrison, E. G., and Clagett, 0. T.: Thymoma-A clinicopathologic study. J. Thorac. Car- diouasc. Surg. 42:424-444, 1961.

4. Bernatz, P. E., Kohnsari, S., Harrison, E. G., Jr., and Taylor, W. F.: Thymoma-Factors influencing prognosis. Surg. Cl in. North A m . 53:885-892, 1973.

5 . Braitman, H., Li, W., Herrmann, C., Jr., and Mulder, D. G.: Surgery for thymic tumors. Arch. Surg.

6. Cohn, L. H., and Grimes, 0. F.: Surgical manage- ment of thymic tumors. Surg. Gynecol. Obstet. 131:206- 215, 1970.

7. Das, P. B., Gupta, R. P., and John, S.: Thymic

103:14-16, 1971.

52 CANCER July 1976 Vol. 38

tumors and their management. Znt. Surg. 58:78&783, 1973.

8. DeMuth, W. E., and Smith, J.: Malignant thy- moina in a child. A m . Surg. 37:742-745, 1971.

9. Efllcr, D. B., and McCormack, I,. J.: Thymic neo- plasnra. J. Thorac. Cardiovasc. Surg. 31:60-82, 1956.

10. Gafni, J., Michaeli, D., and Heller, H.: Idio- pathic acquired agammaglobulinemia associated with thymoma. N . Engl. J. M e d . 263:536-541, 1960.

11. Gravanis, M. B.: Metastasizing thymoma. Ana. J. Clin. Puthol. 49:690~696, 1968.

12. Green, J. D., and Forman, W. H.: Response of thymoma to steroids. Chest 65: 114-1 16, 1974.

13. Grosfeld, J. L., Weinberger, M., Kilman, J. W., and Clatworthy, Jr., H. W.: Primary mediastinal tu- mors in infants and children. Ann. Thorac. Surg. 12:

14. Hamilton, C. R., Jr., and Conley, C. L.: Pure red cell aplasia and thymoma. Johns Hopkins M e d . J. 125:262-269, 1969.

15. Hasncr, E., and Westengard, E.: Thymomas. Acta C h i r . Scand. 126:58-65, 1963.

16. Jacobs, E. M., Hutter, R . V. P., Pool, J. L., and Ley, A. B.: Benign thymoma and selective erythroid aplasia of the bone marrow. Cancer 12:47-57, 1959.

17. Kilman, J. W., and Klassen, K. P.: Thymoma. Ant. J. Szirg. 121:710-711, 1971.

18. Lcgg, M. A., and Brady, W. J.: Pathology and clinical behavior of thymomas. Cancer 18:1131-1143, 1965.

19. Morgan, W. L., and Dudley, H. R.: Malignant thymoma ant1 myasthenia gravis. N . Engl. J. M e d . 253:

20. Mottet, N. J.: Malignant thymoma. A m . J. Clin. Puthol. 41:61-71, 1964.

21. Nathanson, L., Hall, T. C., Rutenberg, A., and Shadduck, R. K.: Clinical toxocologic study of cyclo- liexylamine salt of N,N-bis-(2-chloroethyl)pliosphoro- tliamidic acid (NAS-69945; OMF-59). Cancer Chemo- ther. R e p . 51:35-59, 1967.

179-190, 1971.

625-632, 1955.

22. Clinicopathologic Conference. N. Engl. J. M e d .

23. Ochsner, A., and Bruch, A.: Tumors of thc thy- mus. Surg. C h . Nor th A m . 46:1437-1445, 1966.

24. Platzer, R. F.: Ovalocytosis associated with ma- lignant thymoma. N Y State J. M e d . 7043&432, 1970.

25. Prosnitz, L., Farber, L. R., Fischer, G. L., and Bertino, J. R.: Low dose radiation therapy and com- bination chemotherapy in the treatment of advanced Hodgkin’s disease. Radiology 107: 187-193, 1972.

26. Shields, T . W., Fox, R. T., and Lees, W. M.: Thymic tumors. Arch. Surg. 92:617-622, 1966.

27. Shields, T. W.: T h e thymus gland. Surg. Cl in . North A m . 49:61-70, 1969.

28. Skeggs, D. B. L.: Complications associated with the radiotherapy of thymic tumours. Proc. R . Sac. M e d . 66:155-157, 1973.

29. Soffer, L. J., Gabrilove, J. Id., and Wolff, B. S.: Effect of AC#TH on thymic masses. J. Clin. Endocrinob Metab. 12:690-696, 1952.

30. Stolinsky, D. C., Hum, G. J.. Jacobs, E. M., Solo- mon, J., and Bateman, J. R.: Clinical trial of weekly doses of vinblastine (NSC-49842) combined with vin- cristine (NSC-67574) in malignant lymphoma and other neoplasms. Cancer Cherriother. Rep. 57:477484, 1973.

31. Talley, R. W., O’Bryan, R. M., Gutterman, J. U., Brownlee, R . W., and McCredie, K . B.: Clinical evalua- tion of toxic effects of Cis-diamminedichloroplatinum (NSC-l19875)-Phase I clinical study. Cancer Chemo- ther. R e p . 57:465-471, 1973.

32. Weissberg, D., Goldberg, M., and Pearson, F. G.: Thymoma. A n n . Thorac. Surg. 16: 141-147, 1973.

33. Whitaker, J. A., Vogler, W. R., and Werner, J.: Red cell aplasia and osteoblastic metastasis in a patient with thymoma. Cancer 26:427-435, 1970.

34. Wilkins, E. W., Jr., Edmunds, L. H., Jr., and Castleman, B.: Cases of thymoma a t the Massachusetts General Hospital. J. Thorac. Cardiovasc. Surg. 52:322- 330, 1966.

288~729-733, 1973.