Effect of Radiation Therapy for Urologic Cancer on Circulating Thymus-Derived Lymphocytes

Vol. 112.

THE JOURNAL OF UROLOGY

Printed in

Copyri~ht © 1974 by The Williams & Wilkins Co.

EFFECT OF RADIATION THERAPY FOR UROLOGIC CANCER ON CIRCULATING THYMUS-DERIVED LYMPHOCYTES WILLIAM J. CATALONA, CLAUDE POTVIN*

AND

PAUL B. CHRETIEN

From the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore and the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

It is generally accepted that host resistance influences the clinical course of patients with cancer. It follows that therapeutic manipulations, such as radiation therapy which has the potential to suppress host resistance, may adversely affect the host-tumor relationship. Extensive clinical trials are currently underway which incorporate radiation therapy as an adjunct to surgery for a variety of urological tumors but the value of this therapy remains questionable. Furthermore, the effects of radiation therapy for urologic tumors on host immunocompetence are also unknown. However, it is relevant that an increased incidence of visceral metastases 1 • 2 and an increased mortality 3 were demonstrated following adjunctive radiation therapy for breast cancer and, in at least 1 study, a diminished survival was reported in patients with renal cell carcinoma who received postoperative irradiation when compared to patients treated with nephrectomy alone. 4 These observations suggest that the immunosuppressive consequences of adjunctive radiation therapy may outweigh its benefits and, thus, the importance of monitoring the immune response in patients receiving radiation therapy for urologic cancer is readily apparent. BACKGROUND

The 2 fundamental types of immunologic responses known to exist are humoral and cellular. Each type is mediated by a distinct subpopulation of lymphocytes. Humoral immunity involves circulating antibodies which are produced by B lymphocytes (so called because antibody-producing cells are bone marrow derived). Cellular immunity is mediated by thymus-derived, or T lymphocytes, and involves delayed hypersensitivity reactions, Accepted for publication February 22, 1974. Editor's note. This paper was awarded a prize in the essay contest sponsored by the American Urological Association. * McEachren Fellow, Canadian Cancer Society. 1 Peterson, R. and Russell, M. H.: Clinical trials in malignant disease. III. Breast cancer: evaluation of postoperative radiotherapy. J. Facult. Radio!., 10: 174, 1959. 'Dao, T. L. and Kovaric, J.: Incidence of pulmonary and skin metastases in women with breast cancer who received postoperative irradiation. Surgery, 52: 203, 1962. 'Bruce, J.: Operable cancer of the breast. A controlled clinical trial. Cancer, 28: 1443, 1971. 4 Peeling, W. B., Mantell, B. S. and Shepheard, B. G. F.: Post-operative irradiation in the treatment of renal cell carcinoma. Brit. J. Urol., 41: 23, 1969. 261

transplant (homograft) rejection and tumor-inhib. iting immunity. These 2 types of lymphocytes can be identified in vitro on the basis of differences in their surface properties. Human T lymphocytes bind uncoated sheep erythrocytes in a formation called a spontaneous or T rosette (fig. 1). In contrast, B cytes require special conditions to form rosettes, namely the presence of complement and

FIG. 1. Appearance under light microscopy of human peripheral lymphocytes forming T rosettes with erythrocytes. Also pictured is non-rosette-forming lymphocyte. Reduced from x450.

sheep erythrocytes coated with antibody. Thef:e are called immune or B rosettes. 5 With the rosette assay it has been demonstrated that radiation therapy for mammary carcinoma induces a prolonged reduction in the proportion of T lymphocytes in the peripheral blood. 6 Inasmuch as T lymphocytes are the primary mediators of tumor-inhibiting immunity, it has been that the radiation-induced T lymphocyte defi ciency may be relevant to the occurrence of distant metastases. 6 Our study was undertaken to evaluate T rosetteforming lymphocytes in patients who received radiation therapy for urologic cancer. The results indicate that radiation therapy for urologic cancer 'Wybran, J. and Fudenberg, H. H.: Editorial: mus-derived rosette-forming cells. New Engl. J. 288: 1072, 1973. 'Stjernsward, J., Jondal, M., Viinky, F., Wigzell, H. and Sealy, R.: Lymphopenia and change in distribution of human B and T lymphocytes in peripheral blood induced by irradiation for mammary carcinoma. Lancet, 1: 1352, 1972.

CATALONA, POTVIN AND CHRETIEN

262 TABLE 1.

Peripheral blood total and T rosette-form inf{ lymphocytes in non-irradiated compared to irradiated urolof{ic cancer patients :s.Io.

Mean Age

Total Lymphocyte Count (per cu. mm.) .L S.E.M.

14

1.987 ± 206 2.310 f U90 1.915 :::: 225 2.004 + 160

s2:i • 82t 990 ' 214 81:l i 107t 852 .±. 65t

Non-irradiated urologic cancer patients: Bladder Kidney Prostate Total

;32

69.7 56.0 70.7 69.:l

Irradiated urologic cancer patients: Bladder Kidney Prostate Total

8 4 6 18

64.2 58.0 71.0 65.7

2 16

T Lymphocytes ('7cl ± S.E.M.*

62.:J 61.0 59.4 60.8

= 3.1 ± 6.0 + 8.5 ±- 2.2

53.8 ± :J.2:j: 38.3 ± 8.7:J: 42.:J ± l.5t 46.1 = 2.6t

Absolute T Lymphocyte Count (per cu. mm.) + S.E.M.*

1.201

± 148 1,497 ..L 9:34 1.244 ± 15 1.24:l + 114

439 + 4lt 412 + 146 :145 ± 49t :l96 I 36t

* Standard error of the mean.

t Differs from non-irradiated patients by

p less than .001 by Student's t test. :j: Differs from non-irradiated patients by p less than .05 by Student's t test.

produces a reduction in the number of circulating lymphocytes which is selective for the T cell moiety and which persists for up to 2 years after completion of therapy. The use of adjunctive irradiation should be considered in the light of these findings. METHOD AND MATERIAL

T rosette assay. The method used in this study is a modification of the technique described by Wybran and Fudenberg.' Peripheral blood ( 15 ml.) was drawn into a syringe containing 1,000 units of heparin.* The blood was suspended in 30 ml. magnesium and calcium-free Hanks solution, t and layered on 10 ml. ficoll-hypaque solution made by mixing 20 ml. hypaque:j: with 71 ml. 9 per cent weight by volume ficoll § and 9 ml. distilled water. The samples were centrifuged in 50 ml. plastic tubes II at 400 times gravity for 40 minutes. The mononuclear cells (90 per cent lymphocytes) forming a white disk at the interface above the ficoll-hypaque were pipetted off and washed 3 times in 30 ml. RPMI 1640 tissue culture medium. t The final concentration was adjusted to approximately 2 times 10 6 cells per ml. (about 10 ml.) and 0.25 ml. of the suspension was added to a 15 ml. centrifuge tube containing 0.2 ml. 1 per cent thrice-washed sheep erythrocytes ,i in RPMI 1640 and 0.1 ml. human AB serum which had been heat inactivated at 56C for 30 minutes and absorbed against an equal volume of the same sheep erythrocytes for 30 minutes at 4C. The preparation was incubated at 37C for 15 * The Upjohn Co., Kalamazoo, Michigan 49001. t Gibco, Grand Island, New York 14072. :!:Winthrop Laboratories, New York, New York 10016. § Pharmacia Laboratories, Inc., Piscataway, New Jersey 08854. II Falcon 2070, Falcon Plastics, Oxnard, California 93030. ii National Institutes of Health Animal Center, Poolesville, Maryland 20837.

minutes, centrifuged at 200 times gravity for 5 minutes and then maintained at 4C for 60 minutes before counting. The cell pellet was gently resuspended by tilting the centrifuge tube and 1 drop of 1 per cent toluidine-blue-0** was added to the suspensions for staining. An aliquot of the suspension was drawn by capillary action into a Pasteur pipette and transferred to a hemocytometer. From each sample 200 lymphocytes were counted at a magnification of 450 and the percentage of cells which formed T rosettes was calculated. By convention, any lymphocyte with 3 or more adherent sheep erythrocytes was considered a T rosette. All samples were done in duplicate. Corresponding total and differential leukocyte counts were obtained from which the total lymphocyte count was calculated. Non-irradiated patients. We studied 32 nonirradiated patients with proved urologic tumors. Of these patients 14 had bladder carcinoma, 2 had renal cell carcinoma and 16 had prostatic carcinoma. All patients were preoperative or at least 2 weeks postoperative. Clinical data concerning ages and extent of disease are summarized in tables 1 and 2. Irradiated patients. We studied 18 patients who had received radiation therapy for a variety of urologic tumors. Of these patients 8 had bladder carcinoma, 4 had renal cell carcinoma and 6 had prostatic carcinoma. The clinical data are presented in detail for these patients in table 3 and are summarized in tables 1, 2 and 4. RESULTS

Non-irradiated patients (tables 1 and 2, and fig. 2). As a group non-irradiated urologic cancer patients had a mean total lymphocyte count of 2,004 per cu. mm., a mean percentage ofT lymphocytes of 60.8 per cent and a mean absolute T lymphocyte count of 1,243 per cu. mm. No signifi: ** Fisher Scientific, Fair Lawn, New Jersey 07410.

RADIATION THERAPY FOR UROLOGIC CANCER TABLE

2. Correlations amonf{ clinical staf{e. peripheral blood total and T rosette-forminf{ lvmphocyte counts in

non-irradiated and irradiated patients with urolof{ic cancer

Primary Tumor

Bladder: '.'Jon-irradiated

Tumor Stage

:1 4 2

1 to 2 :l to 4 Kot staged 1 to 2 3 to 4

Irradiated Kidney: Non-irradiated

Mean Age

>lo.

:,

5

Local Metat:itatic

Irradiated

Local Metastatic

Prostate: 1\ on-irradiated

Irradiated

( q)

Absolute T Lvmphocvte Count (per cu. mm.) = S.E.:vl.* 1.209 = :rn, Ll53 ± 229 905 197 7,1 + 282 526 L 119

1.96, = 426 1.996 = 2,i6 1.;3,55 1_ 2G5 1,29:1 ± 400 89:l 1- 1:16

.'i4.8 ~ 5.9 66.:J 4.6 6:3.0 = 3.6 .59.0 c±. 6.5

53.0 59.0

1.020 3.600 .590 l.:!01 ± II

55.0 67.0 21.0 49.:l ~- 2.6

2.430 124

:2,8::-ii -= 586

62.11 .58.8

1.771 1.112

:,8.0 :l l :i :1 :1

T Lymphocytes

1:1.5 62./5 62.5 6,5.7 64.2

60.0

Local Metastatic Local Metastatic

Total Lymphocyte Count (per cu. mm.I ~ S.E.:vI. *

,6.0 69., G'i .ll 7.'i.O

56.2 , 4.1

L /S4 ~ :20'";t 889 ± 211 1:=r1

_1:

594 TH

0

= 4.:J

40.'i 44.0

87

563

s

Li 2.:J

= :JG:i 1,2

:)6;)

= 91

:,28

:i(i

* Standard error of the mean. tDiffers from non-irradiated patient~ with localized disease by p les:-s than .05 b_\· Student's t test. TABLE

3. Correlations amonf{ clinical data and total and T rosette-forminf{ peripheral lymphocyte counts in patients

irradiated for urolof{ic cancer

Pt. Age

6, 6;] 6,

.58 GJ 6'',)

67 68 (ii)

5:1 ;il

60 6,1

65

71 80 84 61

Prirnarv

Tumo;

Blaclcler Bladder Bladder Bladder Bladder Bladder Bladder Bladder Kidnc_\ Kidney Kidne~· Kidnc_\ Prostate Prostate Prostate Prostate Prostate Pro~tate

Tumor Stage

Cumulative Tumor Dose (rads I 4,500

2 :2 :l 4 4 j

2 4 4 4

4,000 4.()00 :i.000 5.500

800 4.-'100 960

:i.0011 9,00IJ 6,0011 2.000

,.2110 :1 -l -! 4

'7,000 :J,000 :l.000 :l.000 11.111111

Radiation Source

Co 60 Co 60 Co 60 Cs 1:1, Co 60 Co 60 Co GO Co 611 Co60 Co 60 Co 60

Co 60 Linear accelera tor Co 60 Co 60 Co 60 Co 60 Co 60

cant differences in total lymphocytes, percentage of T lymphocytes or total T lymphocytes were demonstrated among the various tumor types studied. Irradiated patients (tables 1 to 3 and fig. 2). Virtually all patients who had completed a course of radiation therapy within 1 year of testing manifested a marked depression of the total and T lymphocyte counts. There was also a significant reduction in the proportion of the T lymphocytes in the vast majority of irradiated patients studied, indicating a selective loss from the T cell moiety of the lymphocyte population. As a group patients irradiated within 1 year of testing had a mean total lymphocyte count of 852 per cu. mm., a mean percentage of T lymphocytes

Site Irradiated

Blaclcler Blaclcler Bladder Vagina Bladder Bladder Abdomen Lung Kidney Bone Berne Bone Prostate Prostate Prostate Bone Bone Bone

Interval From Completion of Radiation Therapy (mos.)

Total Lymphocvte Count (per cu. mm.I

12 60

690 1.140 2.0:,0 ,00

66 46 6;) S4

1.:J80

,0

940

564

:i90

60 48 49 21

].:320

4-5

1.060 1.240 980

49 54 ;,8

S9.J: 519 (i,il

2 24 Incomplete

590

Incomplete 1

:JG 2

Incomplete Incomplete 1 12

880

Absolute

TLvmphocytes (%)

48,

41

1.200 ,:11

4;3

890

S90

41 49 12

Count (per cu. mm.J -15;~} -~24

1.:i::n :l,8 966 28:l 4:11 124

:r;-:2 200 "Hi

300 .j;J(i

l-Hl

of 46.1 per cent and a mean absolute T lymphocyte count of 396 per cu. mm. When compared by the standard error of the difference between means to the non-irradiated cancer patients, irradiated patients had significantly lower mean values in all 3 categories. No statistically significant differences were demonstrated among the various tumor types studied. Interval from irradiation to testing (table 4 and fig. 3). Dividing irradiated patients according to the interval between the completion of radiation therapy and the time of testing, no significant recovery of the radiation-induced lymphocyte deficiency was observed before 24 months. Of :3 pa tients with intervals of 24 months or more 2 had normal total lymphocyte and T cell levels and l

264 TABLE 4.

CATALONA, POTVIN AND CHRETIEN

Relation between the interval from completion of radiation therapy to testing, and peripheral blood total and T rosette-forming lymphocyte counts in patients irradiated for urologic cancer Total Lymphocyte Count (per cu. mm.) I S.E.M.*

No.

4 8 3

Radiation therapy incomplete 0 to 6 mos. 7 to 12 mos. More than 12 mos.

938 808 930 1,557

3

± ± ± t

T Lymphocytes (%) ± S.E.M.*

Absolute T Lymphocyte Count (per cu. mm.) ± S.E.M.*

48.2 -t- 4.3 48.8 ,_ 4.1 4o.6 ± 2.0 63.0 ± 4.7*

453 + 08 406 I 53 401 ± 81 990 ± 192t

98 106 172 250*

* Standard error of the mean. tDiffers from patients with intervals of less than 12 months by p less than .01 by Student's t test. EFFECT ANO

OF

RADIATION

THYMUS

DERIVED

NON- IRRADIATED

THERAPY ON

TOTAL

LYMPHOCYTES

IRRADIATED

CANCER PATIENTS

CANCER

PATIENTS

B l

T

2000

T-LYM",t_S

TOTAL LYMPHOCYTES

j

1ympnoc1te-s

E

E

G

1000

'

BLAOOER

8

KIDNEY 4

PROSTA,E

6

FIG. 2. Effect of radiation therapy on peripheral blood total and T rosette-forming lymphocytes in patients with urologic cancer.

had intermediate levels (table 3). All parameters, namely total lymphocyte count, percentage of T cells and absolute T cell count, were significantly lower in 15 patients whose intervals from irradiation to the time of testing were less than 24 months. Relation to tumor stage (table 2). There was a trend toward lower absolute T cell counts among non-irradiated bladder and prostatic cancer patients with advanced disease. The following are the relative distributions of tumor stages among the irradiated and non-irradiated patients. Among bladder carcinoma patients the proportions with advanced disease were 57 and 62 per cent in the non-irradiated and irradiated groups, respectively. The proportion of patients with advanced disease was actually higher among the non-irradiated prostatic cancer patients (81 per cent) than it was among those who had been irradiated (50 per cent). Of the 2 non-irradiated renal cell carcinoma patients studied, 1 had a localized tumor and the other had distant metastases. Of the 4 irradiated renal cell carcinoma patients studied 3 had metastatic disease. However, the most severe lympho-

cyte deficiency was observed in a patient irradiated preoperatively for a localized tumor (tables 2 and 3). Thus, it is apparent that the differences demonstrated between irradiated and non-irradiated patients were not attributable to differences in the distributions of tumor stages between groups. DISCUSSION

The dramatic success of the multidisciplinary approach to the treatment of cancer in tumors such as Wilms tumor has provided a stimulus for increasing use of adjunctive radiation therapy for its tumorcidal potential often without sufficient recognition of the importance of its effects on host resistance. The observation that tumors constantly shed cells into the circulation even in patients with curable cancer 7 indicates that host defenses have the capacity to deal with the vast majority of these cells. This surveillance mechanism is believed to 7 Engel!, H. C.: Cancer cells in circulating blood; clinical study on occurrence of cancer cells in peripheral blood and in venous blood draining tumour area at operation. Acta Chir. Scand., suppl. 201, p. 1, 1955.

RADIATION THERAPY FOR UROLOGliC CANCER RECOVERY

OF

LYMPHOCYTOPENIA

! T~ l

TOTAL LYMPHOCYTES

T-LYMPI

lymphocytes

2000

E E :, <.)

1000

' "'w f--

>-

l)

0 I

(1_

:,:

~ THERAPY 0-6M0S 7-l2M0S INCOMPLETE

4 INTERVAL

6 FROM

>l2M0S

3

COMPLETION

3 OF

RADIOTHERAPY

FIG. 3. Relation between interval from irradiation to time of assaying peripheral blood total and T rosetteforming lymphocytes in patients with urologic cancer. be primarily a function of the cell-mediated (thymus-dependent) immune mechanism. 8 Furthermore, there is a growing body of evidence which suggests that host cellular imm unocompetence is an important prognostic factor in cancer patients. 9 • 10 Therefore, it is essential to strive to maintain the integrity of host defense mechanisms in planning rational cancer treatment programs. The major contribution of this study is the use of the T rosette lymphocyte assay to show that local radiation therapy for urologic tumors produces a significant and substantial reduction in the number of circulating lymphocytes which is to some measure selective for the T cell (tumor-inhibiting) moiety and which persists for up to 2 years. This observation is of considerable theoretical importance. The rationale for combining therapeutic modalities is that if individual modalities are effective in controlling some tumors, a combination of modalities may prove more effective than either alone. However, our findings suggest that the combination may in fact be less effective than 1 8 Smith, R. T.: Possibilities and problems of immunologic intervention in cancer. New Engl. J. Med., 287: 439, 1972. 'Eilber, F. R. and Morton, D. L.: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer, 25: 362, 1970. 10 Chretien, P. B., Crowder. W. L., Gertner, H. R., Sample, W. F. and Catalana, W. J.: Correlation of preoperative lymphocyte reactivity with the clinical course of cancer patients. Surg., Gynec. & Obst., 136: 380, 1973.

265

modality alone and that a careful reassessment of this attitude may be warranted. Lymphocytes are the most radiosensitive of blood cells with a D 0 of 200 rads. 11 Therefore, a!] doses of radiation used for cancer therapy are sufficient to destroy lymphocytes circulating through radiation fields and are probably cumulative in regard to their effects on immunocompetence. Localized irradiation for carcinoma of the breast, cervix and bladder has been shown to reduce absolute lymphocyte counts by more than a third. 11 ' 12 Hume and Wolf also demonstrated significant lymphocytopenic effect from irradiation of the kidney which receives a large proportion of the circulating blood volume. 13 Opinions regarding the effect of regional radiation therapy on T lymphocyte function are conflicting. McCredie and associates reported an increased proliferative response of lymphocytes to phytohemagglutinin (an index of T cell function) in patients irradiated for carcinoma of the breast or uterine cervix. 11 In contrast, Stjernsward and asso-ciates demonstrated a significant lymphocytopenia, a decreased proliferative response to tohemagglutinin and a reduction in the of T rosette-forming lymphocytes after irradiation for breast cancer. 6 Previous studies from a number of different institutions have shown that cell-mediated immunity (a T lymphocyte function) is impaired significant proportion of patients with cancer and, thus, it is necessary to study nonirradiated cancer patients to determine whether the abnormalities of T lymphocytes are the sole consequence of irradiation or whether they are owing in part to the tumor-bearing state. 14 - 1 ' In a separate communication we demonstrated that patients with urologic cancer have a normal total number of circulating lymphocytes but a cant, although relatively mild, deficiency of T 11 McCredie, J. A., Inch, W.R. and Sutherland, RM.: Effect of postoperative radiotherapy on peripheral blood lymphocytes in patients with carcinoma of the breast Cancer, 29: 349, 1972. 12 Goswitz, F. A., Andrews, G. A. and Kniseley, R. M. Effects of local irradiation (Co60 teletherapy) on the peripheral blood and bone marrow. Blood, 21: 605, 1963. "Hume, D. M. and Wolf, J. S.: Abrogation of the immune response: irradiation therapy and lymphocyte depletion. Modification of renal homograft rejection by irradiation. Transplantation, 5, suppl. p. 117 4, 1967. 1 ' Catalana, W. J., Chretien, P. B. and Trahan, E. E.. Abnormalities of cell-mediated immunocompetence in genitourinary cancer. J. Urol., 111: 229, 1974. 15 Olsson, C. A., Rao, C. N., Menzoian, J. 0. and Byrd, W. E.: Immunologic unreactivity of bladder cancer patients. J. Urol., 107: 607, 1972. 16 Catalana, W. J. and Chretien, P. B.: Correlation among host immunocompetence and tumor stage, tumor grade and vascular permeation in transitional carcinoma. J. Urol., UO: 526, 1973. 17 McLaughlin, A. P., III, Kessler, W. 0., Triman, K. and Gittes, R. F.: Immunologic competence in patients with urologic cancer. J. Urol., 111: 233, 1974. 18 Merrin, C. and Han, T.: Immune response in bladder cancer. J. Urol., 111: 170, 1974.

266

CATALONA, POTVIN AND CHRETIEN

lymphocytes when compared to healthy controls or age-matched patients with benign urological conditions. 19 Irradiation for most urologic tumors, unlike irradiation for mammary carcinoma, does not expose the thymus to heavy doses of irradiation. Therefore, it is instructive to inquire into the possibility that thymus-sparing irradiation may produce less severe effects on the T lymphocyte population. However, our results suggest that irradiation for urologic cancer induces T lymphocyte deficiencies as severe as those reported as a consequence of irradiation for breast cancer. In general, our data are compatible with the findings of Stjernsward showing that radiation therapy' for urologic cancer reduced the total circulating lymphocyte count to less than half of nonirradiated cancer patients. This was accompanied by a 14. 7 per cent reduction in the proportion of T cells in the remaining circulating lymphocyte pool, thus yielding a reduction in the absolute T lymphocyte counts to levels less than a third of those of non-irradiated patients. This depression was most severe among patients with carcinoma of the prostate, perhaps because of the proclivity of this tumor to metastasize to the bone marrow. However, comparable T cell levels were observed among patients with cancer of the bladder and kidney (table 1). Although there was a trend toward lower T cell levels among patients with more advanced disease, the differences demonstrated between irradiated and non-irradiated cancer patients were not attributable to differences in the distribution of tumor stages between the 2 groups. Recovery of the total lymphocyte count and the absolute T cell count after radiation therapy was observed in only 3 patients in whom the interval from irradiation to the time of testing was 24, 36 and 60 months. Two patients whose intervals were 12 months continued to manifest deficiencies in total and T lymphocytes (tables 3 and 4). Much of what can be concluded from this study in regard to its clinical relevance in terms of limiting neoplastic growth is extremely speculative. However, as a consequence of the selective reduction of the T cell moiety of lymphocytes induced by radiation therapy, one would expect host-tumor inhibiting defenses to be compromised and the prospects for implantation and clonal outgrowth of circulating tumor cells to be enhanced. This hypothesis is supported by the demonstration of Hume and Wolf 13 that local radiation therapy can abrogate the homograft (transplantation) reaction, a reaction which is analogous to tumor-inhibiting immunity. The recent work of O'Toole and associates is relevant to several issues considered in this 19 Catalona, W. J., Potvin, C. and Chretien, P. B.: T lymphocytes in bladder and prostatic cancer patients. J. Urol., 112 (Sept.) 1974.

report. 20 , 21 These investigators used an assay which detects cytotoxic activity against bladder cancer cells growing in tissue culture by lymphocytes from patients with bladder cancer and demonstrated that definitive radiation therapy abolished or reduced the tumor-inhibiting lymphocyte activity in all patients tested. Moreover, failure of the cytotoxic response to recover soon after the completion of therapy was invariably associated with the development of distant metastases or local recurrence. In contrast, metastases did not develop in patients whose lymphocytes were strongly cytotoxic after therapy during a 1-year period of observation. Although the short followup period precludes any definitive statement in regard to tumor cure, this study illustrates the association between radiation-induced immunologic impairment and short-term prognosis in these patients. However, it should be noted that these investigators used a constant lymphocyte to tumor cell ratio in their experiments. Consequently, the radiationinduced lymphocyte deficiencies extant in vivo would not be reflected in the in vitro assay. This may explain the early return of detectable cytotoxic activity in some of their patients. The relative importance of each of the various effects of radiation therapy on the host-tumor relationship remains to be determined. It is possible that the adverse effects on the host immunologic system may be offset by the tumorcidal effects of irradiation but, in any case, one must rely on host defenses to deal with demonstrable circulating tumor cells which have escaped the radiation fields before the initiation of therapy. It is essential that clinicians appreciate that radiation therapy is a 2-edged sword which not only has the capacity to destroy cancer cells but also invariably modifies host resistance to a significant extent for a prolonged period. Further studies will be necessary with careful immunologic monitoring in controlled clinical trials to define the role of adjunctive radiation therapy in the treatment of urologic cancer. SUMMARY

Studies of T rosette-forming lymphocytes, mediators of cellular (tumor-inhibiting) immunity, in 50 patients with a variety of urologic tumors, of whom 18 were irradiated and 32 were not, revealed that local radiation therapy for urologic cancer produces more than a 50 per cent reduction in the 20 O'Toole, C., Perlmann, P., Unsgaard, B., Moberger, G. and Edsmyr, F.: Cellular immunity to human urinary bladder carcinoma. I. Correlation to clinical stage and radiotherapy. Int. J. Cancer, 10: 77, 1972. 21 O'Toole, C., Perlmann, P., Unsgaard, B., Almgard, L. E., Johansson, B., Moberger, G. and Edsmyr, F.: Cellular immunity to human urinary bladder carcinoma. II. Effect of surgery and preoperative irradiation. Int. ,J. Cancer, 10: 92, 1972.

RADIATION THERAPY FOR UROLOGIC CANCER

number of circulating lymphocytes and more than a 68 per cent reduction of the T lymphocyte moiety which persists for up to 2 years. The results suggest that the systemic immunosuppressive consequences of adjunctive radiation therapy may in-

267

crease the prospects of implantation and clonal. outgrowth of circulating tumor cells. The indications for adjunctive radiation therapy for urologic cancer should be evaluated in the light of these findings.