LOW DOSE FRACTIONATED WHOLE BODY IRRADIATION IN T H E TREATMENT OF

ADVANCED NON-HODGKIN'S LYMPHOMA

NOAH C. CHOI, MD,*.$ ADRIAN R. TIMOTHY, M B , BS,*.$," SHELDON D. KAUFMAN, MD,t*Q ROBERT W. CAREY, MD,t.#

A N D ALAN C. AISENBERC, MDt.5

Thirty-nine patients with advanced non-Hodgkin's lymphoma (38 patients with lymphocytic lymphoma and 1 patient with mixed lymphocytic and his- tiocytic lymphoma) were treated by fractionated low dose whole body irradia- tion (WBI) with a minimum follow-up of 8 months. Twenty-eight patients had no previous treatment and the other 11 patients were in relapse after previous chemotherapy or regional radiotherapy. There were 20 and 19 pa- tients in stages 111 and IV groups, respectively. The majority of patients (31) had nodular histology; diffuse lym'phocytic lymphoma was present in 8 patients (Rappaport criteria) (9). Constitutional symptoms were present in 10 patients. Thirty-three (85%) attained complete remission (CR) with median duration of remission 24 months. Actuarial survival was 78% and 74% at 3 and 4 years. However, relapse free survival was 26% at 3 and 4 years. A prospective randomized trial to compare 10 vs. 15 rad per fraction of frac- tionated WBI schedules (the same total dose 150 rad) demonstrated no dif- ference in response rate, response duration, and median nadir platelet or WBC counts between the two schedules. Supplement radiotherapy to bulky tumor site revented local recurrence, but did not influence survival or dura- tion of remission. Major toxicity was thrombocytopenia with median nadir platelet counts 77,000/mm3 (1 1,000- 170,000/mm3). Five of 6 patients with dif- fuse lymphocytic poorly differentiated lymphoma attained CR. However, their median survival was 30 months which is much shorter than that of nodular lymphoma. Constitutional symptoms and advanced stage (stage 1V) were associated with shorter duration of remission. Response of patients in relapse after WBI to subsequent chemotherapy f local radiotherapy was CR in 50% and PR in 40%. Fractionated whole body irradiation is an excellent sys- temic induction agent for advanced lymphocytic and mixed lymphoma.

Cancer 43:1636-1642, 1979.

P.

ECENT PROGRESS I N THE management of R advanced lymphocytic lymphoma (ALL) has been associated with complete remission rates of 50-85% by either chemotherapy

From the *Department of Radiation Medicine and tDivision of Medical Oncology, Massachusetts General Hospital, and $Department of Radiation Therapy and $Department of Medicine, Harvard Medical School, Boston, Massachusetts.

'I Present address: Department of Radiotherapy, St. Barrholomew's Hospital. London, Englancl.

Address tor reprints: Noah C. Choi, MD, Depart- ment of Radiation Medicine, Massachusetts General Hospital, Fruit Street. Boston, M A 021 14.

'l'he authors thank Dr. Herman Suit for his advice and the initiation of this study. and to Drs. Rita Kelly, William Davies Sohier, Mortimer S. Greenberg and Carnbiz Baher for their care of some of these patients.

Accepted for publication June 12, 1978.

(CVP o r C-MOPP) or whole body irradia- tion~l.J,7,8,10.1t Unfortunately, long-term re- sults have been discouraging with only 20- 24% relapse-free survival at 5 We began to explore the role of whole body irradiation in management of advanced non- Hodgkin's lymphoma in 1972 following the encouraging report of whole body irradiation in advanced lymphocytic lymphoma by John- son et d. in 1970.6 Excellent responses were observed but bone marrow depression charac- terized by thrombocytopenia was recognized as a major limiting factor of this treatment as noted by other^.^.^ This report describes results of a clinical trial designed to evaluate tumor response and tolerance of bone mar- row in patients treated by two fractionation schedules.

0008-543X/79/0500/1636 $0.85 0 American Cancer Society

1636

No. 5 WBI I N ALL . Choi et al. 1637

MATERIALS A N D METHODS

Patients’ Data

Between December 1972 and February 1977, 39 patients with advanced non-Hodg- kin’s lymphoma of lymphocytic and mixed lymphocytic-histiocytic histology were treated by fractionated low dose whole body irradia- tion. Pretherapy evaluation of the patient in- cluded: 1 ) history for weight loss of more than 10% of normal weight, night sweats and un- explained fever, 2) chest x-rays, 3) IVP, 4) liver function tests and liver scan, 5) lymph node biopsy, 6) pedal lymphangiograms (30/39 patients) and 7) bone marrow biopsy (35/39 patients). Patients were staged accord- ing to the 1971 Ann Arbor criteria.’ Distri- bution of these patients according to their age, sex, stage and histology is shown in Table 1. N o patients with chronic lymphocytic leukemia were included. Patients with DLWD histology had involvements of bone marrow and lymph nodes without lymphocytosis in peripheral blood o r splenomegaly.

Ten patients had systemic symptoms; 3 stage 111 and 7 stage IV diseases; and 8 with NLPD and 2 with DLPD histologies.

Nineteen patients were classified as stage I V because of involvement o f bone marrow, 8; bone marrow plus liver, 2; bone marrow plus skin, 1; lymph nodes plus skin, breast, pleura, and/or bone, 8.

Eleven patients had had previous treat- ments: single agent or multidrug combina- tion chemotherapy for 2-24 months, 5 pa- tients; local and regional radiation therapy, 3 patients; and local radiation therapy plus chemotherapy, 3 patients. Five of these 1 1 patients had systemic symptoms.

TABLE 1. Patients’ Data

Radiation Facilities and Treatment Set-Up

Fractionated low dose whole body irradia- tion was delivered initially on 2 MeV Van d e Graaff from December 1972 to 1975, and since 1976 Eldorado-78 6oCo teletherapy unit has been utilized. Details of treatment tech- nique was given in Table 2. Dosimetry was based upon dosimetric studies using a phantom.

Median age Sex (MIF) Stage 111

IV Histology

Nodular NLPD

Diffuse DLPD N M

DLLVD

59 (31-80) 18/21

20 I9

30 1 6 2

Distribution of patients according to their age. sex stage and histology. NLPD-nodular lyinphocyrir poorly differentiated. NM-nodular mixed lymphocytic and histiocytic. DLPD-diffuse lymphocytic poorly differen- tiated, DLCVD-diffuse lymphocytic well differentiated.

minister 150 rad in 10 fractions of 15 rad with two treatments per week. This treatment goal was frequently not achieved because of thrombocytopenia which required treatment interruption. We became interested in the use of lower doses per fraction as possibly a better tolerated treatment regime. To ex- amine this problem, a prospective randomized clinical trial has been performed to compare patient’s tolerance and tumor response to whole body irradiation given at 15 vs. 10 rad per fraction. T h e details of the two schedules are given in Table 3. Patients were randomly allocated to treatment Schedule A or B. Eighteen patients have been entered into this study and the minimum follow-up is 8 months.

Analysis of Data

Survival was calculated from the start of WBI to the time of this analysis or of the patient’s death. Duration of response was

TABLE 2. Treatment Techniques for Whale Body Irradiation

Eldorado 78 Van de Graaff ROC0

Field Parallel opposed Parallel opposed right and left anterior and lateral posterior

cin x 76 cm box. Bolus around ex- tremities and head

Position Patient in a 76 Standing

Distance (SAD) 250 457

Oose rate (rad 5.5 = 6.0 4.5 = 5.0

in cm

min.-’)

Fractionated Whole Body Irradiation Schedule

Our early patients were treated on a dose fractionation’ schedule which aimed to ad-

1638 CANCER ,May 1979 Vol. 43

TABLE 3. Dose Fractionation Schedules for Whole Body Irradiation

Schedule A Schedule B

Total dose (D) rad 150 I50

Number of fraction$ (v) 10 15 Total time (I') weeks 5 5

Dose per fraction (D,) 15 10 Treatments per week 2 3

measured from the completion of WBI to the first objective evidence of relapse. Complete remission is defined as complete clearance of all demonstrable diseases by clinical restag- ing procedure; ~ i z . , physical examination, chest x-rays for mediastinal and hilar tumors. and follow-up KUB x-rays to evaluate retro- peritoneal lymph nodes demonstrated by previous lymphangiograms. Partial remission is defined as more than 50% clearance of de- monstrable tumors for a period of 3 months. Only 2 of 1 1 patients with initial positive marrow underwent repeat bone marrow biopsy after \.VBI. Repeat biopsies of hone marrow or liver were not done as a part of restaging procedure. Statistical methods used include life table methods for survival and relapse free survival curves, Chi-square test for the differences in remission, and a generalized Wilcoxon test for relapse rate.4

RES LILTS

Thirty-nine patients have been treated and none have been lost LO follow-up. Treatments received by these patients were: median total dose 150 rad (40- 160 lad), median number of treatments 10 (4- 15) and median duration of treatments 38 days (15-75 days).

~

H

Thirty-three of 39 patients (85%) attained complete remission (CR) and 6 other patients (15%) attained partial remission (PR). T h e median induction period for complete remis- sion was 6 weeks (1 -4 months) from the com- pletion of WBI.

Survival and Relapse-Free Survival

T h e actuarial survival curve calculated for all 39 patients is shown in Fig. 1 ; the 3 year sur- vival rate is 78%. In contrast, the relapse-free survival curve is quite steep with only 26% of the patients being relapse-free at 3 years. Twelve of 33 patients who attained CR have not relapsed. The median relapse-free survival time is 24 months (8-49 months).

Histology and Response to WBI

Twenty-six of 31 patients (84%) with nod- ular lymphoma (30 patients with NLPD and 1 patient with N M ) attained CR with median duration of remission 24 months (2- 46 months). 'Their actuarial survival is 79% and 73% at 3 and 4 years as shown in Fig. 2. One patient with nodular mixed lymphocytic and histiocytic lymphoma attained CR which lasted 40 months. However, her tumor re- curred in the right breast and axilla which were the initial major sites of presentation. Local radiotherapy to these areas achieved another complete remission. Five of 6 pa- tients with diffuse lymphocytic poorly dif- ferentiated lymphoma (DLPD) had CR with median duration of remission 20 months (5- 26 months). However, their survival curve has a steep slope with only 50% survival rate at 30 months. Because of small numbers in DLPD

FIG. I . Actuarial survival and relapse-free survival following fractionated whole body irra- diation.

0 0 6 42 48 24 30 36 4 2 48 54

M0NrH.s

No. 5 WBI I N ALL * Choi et al. 1639

i 00

FIG. 2. Actuarial survivals by histology following fractionated

a trend of better survival in nodular histology.

whole body irriidiation. There is

20

"0 6

group, no statistical test was made. Two other patients with DLWD histology also attained CR with remission duration 49 and 52 months.

Ten vs. Fifteen Treatments of Fractionated WBI Schedules

Eighteen consecutive patients were random- ized into the control and study fractionated WBI schedules with 9 patients in each group (Table 3). T h e two groups were comparable with respect to numbers of patients with NLPD histology (8 and 9); however, group B had more patients with stage IV (6 vs. 3) and with B symptoms (4 vs. 1). T h e t w o groups did not differ in median nadir platelet or WBC counts (Table 4). CR rates were similar for the two groups. However, median dura- tion of CR was 18 months (2-34 months) and 8 months (4-24 months) for groups A and B, respectively. However, this difference could have been as a result of more patients with B symptoms and with stage IV disease i n the study group.

Response to WBI by Stage and Systemic Symptoms

In order to evaluate the significance of stage and presence or absence of systemic symp- toms in response to WBI, 30 patients with NLPD histology were analyzed for their re- sponse to WBI (see Tables 5, 6). Complete remissions were attained in 15 of 17 patients (88%) and 10 of 13 patients (77%) with stages I11 and IV, respectively; the difference be-

I2 48 24 30 36 42 48

MONTHS

tween 15/17 and 10/13 is not significant. How- ever, median duration of remission was 24 months for stage 111 but only 13 months for stage IV groups, p < 0.05. Subsequent treat- ments with chemotherapy ? local radiother- apy for those with the relapse (stage IV) pro- longed their survival equal to that of stage 111 group.

With respect to systemic symptoms, com- plete remission was attained in 5 of 8 pa- tients (63%) and 20 of 22 patients (91%) with and without systemic symptoms, respectively (Table 5). This difference is not significant. However, the median duration of remission was 10 months and 24 months for those with or without systemic symptoms, p < 0.05. Sur- vival of those with systemic symptoms was as good as those without them as a result of their good response to subsequent treatments with chemotherapy -C local radiotherapy.

T A B L E 4. Hematological 'I'olerance and Tumor Response

,4 R Schedule Control Study

~

Platelet counts 6'2 x 10" 55 x 1 0 ' (24- 170) l o J (20-139) 10s

(1.6-4.8) 103 (.9-4.0) 1 0 3 WBC 3.3 x 103 3.0 x 1 0 3

Response CR a19 819 PR I I9 I19

Median WBC and platelet counts per n11n3 with ranges in parenthesis. CR-complete remission. PR-partial remission.

1640 CANCER M q 1979 Vol. 43

TABLE 5. Response of Patients with NLPD Histology to WBI by Stage

Complete Duration of remission remission Survival

Stage 111 15/17 (88%) 24 M 30 M Stage 1V IN13 (77%) 13 M 24 M

Previous Treatments and Response to WBI

Eleven patients were treated with WBI for relapse after the previous treatments which in- cluded chemotherapy in 5 patients, local or regional radiotherapy in 3 patients and local radiotherapy plus chemotherapy in 3 other patients. Histology of these patients included NLPD in 10 patients and DLPD in 1 patient. Systemic symptoms were present in 5 of the 1 1 patients. Five of 6 patients without systemic symptoms attained CR with median duration of remission 25 months (13-40 months). However, only 1 of 5 patients with systemic symptoms attained CR and the other 4 pa- tients attained partial remission. Median dura- tion of remission of these 5 patients was 4 months (2- 18 months) which is significantly shorter than that of those without systemic symptoms, p < 0.05.

Response of Relapse After WBI to Further Treatments

Twenty-five patients who received further treatments for relapse after WBI were avail- able for assessment of their response to the subsequent treatments (Table 7). Overall re- sponses were 525% of CR (13/25) with me- dian duration of remission 9 months (2-36 months), 44% of PR (1 1/25j with median dura- tion of remission 4.5 months (1 - 12 months) and no response in 1 patient. Twelve of 20 patients in relapse with NLPD histology at- tained CR and 7 other patients attained PR. One of 5 patients with DLPD histology at- tained CR and 4 other patients attained PR.

TABLE 6. Constitutional Symptoms and Response to WBI in Those with NLPD Histology

Complete Duration of remission remission Survival

A (22) 20/22 (91%) 24 M 29 M €3 (8) 5/8 (63%) LO M 30 M

A and B represent absence or presence of constitu- tional symptoms.

Supplement Radiotherapy and Pattern of Relapse

Supplement radiotherapy was given to neck, axilla, groin and mediastinum for residual tumor. Radiation dosages were in the range of 400 to 3000 rad given at daily doses of 200 and 250 rad. As shown in Table 8, re- lapse at bulky sites was reduced from 43% (12/28) to 0% (0/11) by the supplement radio- therapy. However, no difference was noted in terms of relapse-free survival rate. Median duration of remission was shorter with supple- ment radiotherapy than without it; patients who received supplement radiotherapy had more extensive presenting disease than those not given supplemental doses.

Toxicity

These treatments were well tolerated and was administered as an out-patient basis. Sys- temic side effects during treatments were slight loss of appetite and mild fatigue. All patients who worked prior to the initiation of WBI, continued their work during this treatment. The major toxicity was hematologic with median nadir platelet counts of 77,000/ mm3 (1 1,000- 170,000/mm3); 12 of 39 pa- tients (31%) had platelet counts less than 50,000/mm3. One patient was given platelet transfusion. There was no incidence of serious hemorrhage, other than focal sub- cutaneous homorrhages in a few patients. T h e median nadir leukocyte count was 3,700/ mm3 (550-7,300/mm3); with 6 of 39 patients had WBC <2000/mm3. Leukopenia with leu- kocyte counts less than 1,500/mm3 was noted in only 3 of 39 patients (8%). Five of 6 pa- tients with WBC less than 2,000/mm3 had con- comitant thrombocytopenia. N o patient had infectious complication at the nadir of radia- tion induced leukopenia. Three patients had prolonged bone marrow depression which made subsequent chemotherapy difficult. However, 2 of these 3 patients had progres- sion of lymphoma into the bone marrow. Clinical parameters of 12 patients with throm- bocytopenia included: bone marrow involve- ment in 6 patients (6 of total 12 patients with positive bone marrow); stage I V disease in 8 patients (8 of total 19 patients with stage IV tumor); and B symptoms in 3 patients (3 of 10 patients with B symptoms). There has been no recognized radiation related late com- plication. There were 7 patients with age 70 years or older; 6 patients tolerated WBI well

No. 5 WBI I N ALL * Choi et ai. 1641

with median dose 150 rad (105-150 rad). T h e other patient was given only 40 rad of WBI followed by supplement mediastinal radiation for huge mediastinal lymphoma associated with pleural effusion.

DISCUSSION T h e primary objective of this study was to

explore the role of low dose fractionated WBI in management of stages 1 1 1 and IV non-Hodgkin's lymphoma, excluding his- tiocytic lymphoma. High complete remission rate (84%) with a median duration of re- mission of 24 months represents a good therapeutic result with this disease; it also confirms reports by other author^.^.^ Multi- agent chemotherapy (CVP or C-MOPP) has been reported to attain similar response rate and duration of remission of WBI.8-10 T h e recent NCI randomized trial which com- pared WBI with CVP or C-MOPP chemo- therapy in patients with previously untreated lymphocytic lymphoma demonstrated com- plete remission 85% (28/33), and 62% (26/42) with median duration of remission 26 months and 22 months for fractionated WBI and com- bination chemotherapy, respectively."

In terms of simplicity of treatments and morbidity, fractionated WBI is much better than combination chemotherapy. Fractionated WBI is given twice weekly for 5 weeks with 10 treatments. Blood counts are done once weekly for the first 3 weeks and then twice weekly before each treatment for the last 2 weeks. Thrombocytopenia with nadir platelet counts less than 50,000/mm3 was noted in 30% of patients. Induction program of CVP chemotherapy includes 6 cycles of chemo- therapy with 1 cycle every 3-4 weeks in most patients and 12 cycles in some patients." Thirty-six percent (18/50) of patients re- quired hospitalization at some point during therapy for leukopenia or documented in- fection. T h e severity of the leukopenia ap- pears greater than that from fractionated WBI in the dose levels employed." Luce U I (11. reported 1-2% of mortality related with CVP chemotherapy.* Myelogenous leukemia as a late complication of fractionated WBI was found in patients who received further treat- ments with repeat WBI and chemotherapy or TNl prior to WBI." N o TNl was given in addition to WBI in the present series; 1 patient received a second course of WBI for relapse. N o patient has developed myelog- enous leukemia to date.

TABLE 7. Treatment Response for Relapse Following WBI

______ ~~

Further therapy CR PR NR TOTAL

Cyclophosphamide, Vincristine & Prednisone 3 6 1

Chlorambucil & Prednisone 1 2 -

Chloram bucil 2 1 - Vincristine &

Prednisone 1 - - C yclophosphamide I - - Radiotherapy & CVP I - - Local radiotherapy 3 2 - WBI I - -

TOTAL 13 I 1 1

10

3 3

1 1 1 5 1

25

Relapse rate has been high for both frac- tionated WBI and CVP or C-MOPP chem- otherapy. At 4 years after initial CVP or C-MOPP chemotherapy, 24% of nodular and 13% of diffuse lymphocytic lymphoma re- mained free of disease, viz., the same result achieved by fractionated WBI at NCI, the Joint Center for Radiation Therapy and in the present report.5J1

Response of diffuse poorly differentiated lymphocytic lymphoma to chemotherapy has been in the range of 13%-22% complete remission by either single agent or multidrug chemotherapy with median duration of remis- sion 1 1 - 12 months.10." O n the other hand, \VBI achieved complete remission in 5 of 6 patients and 1 1 of 16 patients in this and NCI series, respectively, with median dura- tion of remission 17-20 months." Despite the initial good response to WBI, survival was rather poor, 50% at 30 months.

Other prognostic factors were stage and constitutional symptoms. T h e duration of remission of those with stage IV tumor or B

TABLE 8. Supplement Radiotherapy and Pattern of Relapse

With Without supplement supplement

radiotherapy radiotherapy

No. of patients 1 1 28 Relapse of bulky sites 0 12

relapse 4 8 No. of patienrs with

Duration of median remission 13M 22M

(2-30) (2-52)

1642 CANCER May 1979 Vol. 43

symptoms was significantly shorter than that of those with stage 111 tumor or without B symptoms. However, their survival was equally good as others with stage 111 tumor or without B symptoms because of their good response to subsequent chemotherapy 5 local radiotherapy.

Our trial to modify the degree of throm- bocytopenia by more frequent treatments using 50% less dose than the standard dose per treatment to the same total dose was not successful. It would be interesting to explore intermittent low dose rate WBI in a fashion

as intermittent high dose chemotherapy is given.

In conclusion, fractionated low dose rate WBI is an excellent induction agent for stages 111 and IV nodular as well as diffuse Iymphocytic lymphoma. In view of the good response (CR 50%, PR 40%) of the relapse after WBI to the subsequent chemotherapy 2 local radiotherapy, maintenance chem- otherapy after WBI may be of value in pro- longing duration of remission and possibly improving survival.

REFERENCES

I . Bagley, Jr.. C. M.. DeVita, Jr.. V. T., Berartl. C. W.. and Canellos. G . P.: Advanced lymphosarcoiiia: Intensive cyclical combination chemotherapy with cyclophosphainide, vincrisiitie and prednisone. Atttt.

I t i / u r i . ,Mrd. 76:227-234. 1972. 2. Carbone, P. P., Kaplan, H. S.. hlusshoff, Ii.,

Smithers, D. b'., and Tubiana, hi.: Report of the com- mittee on Hodgkin's disease staging classification. (,'nriwt.

3. (:haffey. J. '1. .. Rosenthal. D. S.. Moloney. \V. C., and Hellnian. S.: Total body irradiation as treatment for lyinphosa~coina. ! t i / . J . Rod. Otirol. Biol. P / i u . I :3W- 405, 1976.

4. Gehen, E. A,: A generalized Wilcoxori test for coni- paring ;irbitrariIy singly censored wnples . Hiotttc/riho

5. Hellman. S., Ctiaffey, 1 . T., Rosenthal, L). S., Moloney, W. C.. Canellos. G . P.. and Skarin, A. T. : 'l'he place of radiation thei-apy in the treatitlent of non- Hodgkin's lyinphoiiias. (;crrtrrr 39:843-85 I , 1977.

6. Johnson, K. E., O'Conor, G . T., and Levin. D.: Primary management of advanced lyniphosarcoina with rddiother.dpy. ~ / r r / ( . r t . 25:787-701, l970.

R t > . 31:IX60-I861, 1971.

523203-233, IYti5.

7. .johnson. R. E.: Total body irradiation (TBI) as priinary therapy for advanced lymphosarcoma. Cancer 35249-246. 1975.

8. h c e , . I . K.. Gainble, J. F.. Wilson, H. E., Monto, K. W.. Issacs. B. L.. Palmer, R. L., Coltman. Jr.. C. A,. Hedet t . J . S. , Gehan. E. A,. and Frei. E.. I l l : Com- bined cyrlophosphamide, vincristine, and prednisone therapy of malignant lymphoma. Cnrirrt. 28:306-3!7. 197 I .

9. Rappaport, H.. Winter, W. F., and Hicks, E. R.: Follicular lymphoinas: Re-evaluation of its position in t tic wheiiie of malig~iant lvmphomas. based on survey of 253 ciises. (,'nrtwt. 97W-821, 1956.

10. Skxiin. A, , Pinkus, G. S., hlyerowitz. R. L., Bishop, Y . M., and Moloney, N'. C.: Coinbination chem- olhel.apy of advanced Iyriiphncytic lymphoma. Caizrrr :34:1023-1029. 1974.

1 I . Young, R. C., Johnson. R. E., Canellos. G . P.. Chal)ner, B. A.. Brereton, H. D., Berard, C. W., and DeVita, V. 'I . . : Advanced lyniphocytic lymphoma: Ran- doinized coniparisons of chemotherapy and radio- thempy. ;ilorir or in rombinaiioii. C f i i i w r 7 r ~ d . Rep. 61 : 1133- 1159. 1977.