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??Original Contribution

THE PALLIATION OF BRAIN METASTASES IN A FAVORABLE PATIENT POPULATION: A RANDOMIZED CLINICAL TRIAL BY THE RADIATION

THERAPYONCOLOGYGROUP

JOHN M. KURTZ, M.D., * RICHARD GELBER, PH.D.,-! LUTHER W. BRADY, M.D.,* RICHARD J. CARELLA, M.D.$ AND JAY S. COOPER, M.D.9

The palliative effectiveness of a short, intensive course of brain irradiation (3000 rad in 2 weeks) was compared to that of a high-dose course (5000 rad in 4 weeks) in a randomized RTOG clinical trial. Eighty percent of the 255 evaluable patients had lung primaries, 7% breast, and 13% other or unknown primaries. Patients with evidence of extra-cranial metestases, uncontrolled primaries, or Class IV Neurologic Function (NFIV) were excluded. Forty-one percent of NFII and 71% of NFIII patients improved in neurologic function class. For NFII patients, a significantly greater improvement rate was obtained with the short course than with the long course. Otherwise there were no significant differences between the two regimens with respect to palliation of symptoms, improvement rate, median time to progression, cause of death, or median survival. We conclude that 3000 rad in two weeks is at least as effective as 5000 rad in four weeks in the palliation of brain metastases, even in this relatively favorable patient population.

Brain metastases, Radiation therapy, Palliation, RTOG, Fractionation.

INTRODUCTION Radiation therapy has unquestioned value in the pallia- tion of brain metastases.‘.2,6.7.n~9.‘o,“.‘3.‘4 Although specific neurologic symptoms can reliably be alleviated and the survival quality of most patients thereby improved, survival durations still remain extremely limited. Median survivals range from lo-40 weeks, depending on such parameters as primary site, initial performance status and neurologic function class, and presence or absence of apparent extra-cranial disease activity. In approximately one-half of irradiated patients, death is attributed to uncontrolled brain metastases.‘.6 In an effort to improve this apparently high local-failure rate, the Radiation Therapy Oncology Group (RTOG) has investigated several different dose-fractionation schemes in two large randomized clinical trials, the results of which have recently been reported.‘,7 These studies failed to demon- strate any benefit for protracted high dose schedules over the least aggressive program from either the standpoint of median survival or quality of palliation.

Although long-course brain irradiation has no appar- ent superiority in the overall group of patients with

intra-cranial metastases, it is quite possible that sub- populations can be identified which might benefit from more aggressive treatment. A recent retrospective analy- sis of the data from the previous RTOG trials has failed to demonstrate any advantage for any of five treatment schedules even among selected subgroups with favorable survival characteristics.’ This report presents the results of a third RTOG clinical trial which investigates prospec- tively the use of a higher dose schedule compared .with the “best standard treatment” in a highly selected, favor- able group of patients with brain metastases.

METHODS AND MATERIAL

The study population consists of cancer patients with positive isotope brain scans and with no evidence of other sites of disseminated disease. Not eligible for the study were patients of Class IV neurologic function (Table I), those patients who received anti-cancer treatment within the previous two weeks, and those with a progressive untreated primary. Between May 1976 and August 1979, 309 patients were accessioned from 31 participating institutions and randomized between two treatment

*Department of Radiation Oncology, School of Medicine and University Hospital, Seattle, WA 98 195.

TSidney Farber Cancer Institute, Boston, MA 021 IS. *Department of Radiation Therapy and Nuclear Medicine,

Hahnemann Medical College and Hospital, Philadelphia, PA 19102.

$Department of Radiation Oncology, New York University Hospital, New York, NY 10016.

This work was supported by Grant CA21661 from the Division of Cancer Treatment of the National Cancer Institute.

Reprint requests to: John M. Kurtz, M.D., Department of Radiation Oncology, University Hospital, RC-08, Seattle, WA 98195.

Accepted for publication 25 April I98 I.

891

892 Radiation Oncology 0 Biology 0 Physics July I98 I, Volume 7, Number 7

Table 1. Neurologic function class Table 3. Cause of death

Class I: Able to work, neurologic findings minor or ab- sent.

Class II: Able to be at home although nursing care may be required. Neurologic findings present but not serious.

Treatment (rad/wks)

Class 111: Requiring hospitalization and medical care with major neurologic findings.

Class IV: Requiring hospitalization and in serious physical or neurologic state including coma (not el- igible for this study).

Cause of death Total 3,000/2 5,000/4

Brain metastases II4 (53%) 58 (54%) 56 (52%) Cancer at other sites 53 23 30 Other 34 21 I3 Unknown 13 5 8

214 107 107

options. Fifty-four (17%) patients were ineligible or cancelled (primarily because of multiple metastatic sites), leaving a study group of 255 evaluable cases.

Accrual by treatment option is shown in Table 2. Disqualifications were equally numerous in both arms. Treatment was delivered to the whole brain on megavolt- age equipment in all cases, the 3000 rad arm consisting of ten 300 rad fractions, and the 5000 rad arm consisting of twenty 250 rad fractions, extended to a 5 week interval if necessary. Treatment arms were stratified according to primary site and neurologic function. Among the 255 evaluable patients, there were 204 (80%) lung primaries, 18 (7%) breast, I2 (5%) unknown primaries and 21 (8%) “other” (5 colon, 4 melanoma, 4 kidney, 2 stomach, and one each of esophagus, rectum, endometrium, uterine cervix, ovary and prostate). One hundred sixty-eight of the total group (66%) were ambulatory. Seventy-one (28%) patients were in Neurologic Function Class I (NFI), I18 (46%) in NFll and 66 (26%) in Class III; NFIV patients were excluded from the study. Although patients with progressive untreated primary tumors were excluded from this study, only 40% of the evaluable cases were reported to have the primary absent. Steroids were administered during radiation to 67% of the patients, and chemotherapy was administered to 6%. The distribution of patient characteristics is well balanced between both treatment groups.

were made prior to treatment (initial value), weekly throughout treatment, one week post-treatment, at 2 and 3 months, and every 3 months thereafter. Improvement was scored if a decrease in NF Class was the first reported change. Statistical methods were identical to those of the previous RTOG studies.‘,4,5,‘2

RESULTS

Thirty-five patients (14%) failed to complete the protocol treatment, 24 of these because of deterioration or death. Only 9 of the 130 patients (7%) in the 3000 rad/2 weeks arm failed to complete treatment, receiving a median dose of 1800 rad (range 600-2700). However, 26 of the 125 patients (21%) in the 5000 rad/4 weeks arm did not complete therapy, receiving a median dose of 3000 rad (range 250-4750). The duration of treatment was extended beyond 4 weeks for 28 of the 99 patients (28%) who completed the 5000 rad schedule.

Twenty-seven patients (1 1%) received additional non- protocol brain irradiation from 2 to 43 weeks following the end of the initial course of treatment, 20 in the 3000 rad group and 7 in the 5000 rad group.

Survival

Effectiveness of treatment was evaluated in terms of cause of death, median survival from data of randomiza- tion, improvement in Neurologic Function Class, specific symptom relief, and median time to progression. The latter parameter was defined as the median time from the start of treatment to deterioration of neurologic function or death, whichever occurred first. Assessments of status

Two hundred-fourteen of the 255 evaluable patients (84%) have died, 107 in the 3000 rad group and 107 in the 5000 rad group. The causes of death are shown in Table 3. There is no difference between the two treat- ments with respect to altering the pattern of cause of death.

The median survivals according to various patient characteristics are presented in Table 4 and the survival curves in Figure I. The differences in survival according to treatment are not statistically significant, either over- all or within any of the patient subgroups. Thus a higher

Table 2. Patient entry by treatment

Treatment

Patients randomized Cancelled Ineligible

Patients analyzed

Total 3,000 rad/2 wks 5,000 rad/4 wks

309 I56 I53 15 7 8 39 I9 20

255 130 125

Palliation of brain metastases 0 J. M. KURTZ et al. 893

dose of radiation cannot be said to improve survival for these patients. There is a significant prognostic influence of initial performance status and neurologic function, primary site, prior brain surgery, and interval from primary diagnosis to brain metastasis. The effect of prior brain surgery, however, may at least partly be a result of selection factors, since the best survival occurred in patients who had biopsy only, 92% of whom were ambu- latory. Similarly the superior survival of patients having an interval of more than two years between primary diagnosis and brain metastases may reflect the greater proportion of breast cases in this subgroup (33%) than in the study group as a whole (7%). When lung primary

Table 4. Median survival in weeks: (based on 214 deaths-107 in each treatment group)

Total 3,000/2 5,000/4

Total

Primary site Breast Lung Other Unknown

Neurologic function Class I Class II Class II I

Performance status Ambulatory (70-100) Non-Ambulatory (~70)

Both P.S. and N.F. Ambulatory N.F. I Ambulatory N .F. I I Non-Ambulatory N.F. II

18 (255) 18 (130) 17 (125)

53(18) 73(ll) 27(7) 16 (204) 16 (102) 16 (102) 17(21) 16(12) 18(9) 42 (12) 26 (5) 49 (7)

27 (71) 27 (32) 26 (39) 16 (118) 17 (62) 13 (56) 15(66) 15(36) 16(30)

22 (168) 23 (83) 18 (85) 14 (87) 14 (47) 14 (40)

27(69) 27 (32) 26(37) 17 (90) 19 (48) 16 (42) 12 (28) 13 (14) 6 (14)

Non-Ambulatory N.F. III 15 (57) 14 (33) 18 (24)

Status of primary Absent 21 (101) 22 (56) 21 (45) Present or unknown 16(154) 15(74) 16(80)

Prior brain surgery None 16 (203) 17 (105) 14 (98) Biopsy only 50 (13) 24 (5) 55 (8) Gross removal 24(39) 23(20) 23(19)

Steroids during XRT No 22(84) 17(49) 26(35) Yes 17(171) 18(81) 16(90)

Chemotherapy during XRT No 17 (240) 18 (123) 17 (117) Yes 20 (15) 23 (7) 17 (8)

Primary to brain mets interval Less than 6 months 14(106) l3(49) 15(57) 6 months to 2 years 18 (60) 18 (33) IS (27) More than 2 years 27(30) 27(21) 26(9)

Treatment (rad/wks)

Note: No. of patients is given in parentheses P.S. = Performance status.

2- _ _ _ - _ - . _ _

k-

_ _

li 2’4 3’6 48 6b 7i WEEKS

TREATIlEIiT ALIVE DEAD TOTAL MEDIAN - 3000 R,dZ WKS. 23 107 130 18.2 _ _ - 5000 RAD/~ WKS. 18 107 125 16.9

Fig. I. Survival by treatment.

cases are analyzed separately, only performance status has significant effect on survival, with median survivals in ambulatory and non-ambulatory patients of 18 weeks and I3 weeks, respectively.

Palliative benefit Table 5 presents the percentage of patients who

showed improvement in neurologic function score accord- ing to treatment ambulatory status and steroid adminis- tration status. Forty-one percent of NFII patients and 7 1% of NFllI patients improved while on-study. The median time to improvement was two weeks, with 82% of the patients who improved doing so within one month. There was no difference in this rate of improvement between the two treatment arms. For initial NFII patients a greater frequency of improvement is seen for the 3000 rad group than for the 5000 rad group (two- sided p = 0.04, Fisher’s exact test).l However, the reverse trend is seen for the NFIII patients. Initial performance status is an important prognostic factor for NFII patients, ambulatory patients improving more frequently than nonambulatory. There are too few ambulatory NFlll patients to adequately judge the significance of this factor within this subgroup. Within neurologic func- tion class, no other patient characteristics were found to be important predictors of response. The rate of improve- ment was similar for patients receiving or not receiving steroid therapy.

The specific symptoms of headache, nausea, vomiting, convulsions, motor loss, cerebellar symptoms, cranial nerve involvement, dysphasia, incontinence and impaired mentation were monitored throughout the study. Table 6 indicates the frequency of improvement in some of the more common symptoms. There is no statistically signifi- cant advantage of one treatment over the other with respect to symptom relief. The influence of steroids on the rate of relief of headache and motor loss was analyzed, and no significant effect was found. The rates

894 Radiation Oncology ??Biology 0 Physics July 1981, Volume 7, Number 7

Table 5. Percent of initial N.F. II and N.F. III patients with improvement in neurologic function

Treatment (rad/wk)

Initial neurologic

function

Total 300012 5000/4 .___

No. % No. % No.

N.F. II

N.F. 111

N.F. II + III

Total Ambulatory Non-ambulatory Steroids during XRT No steroids

Total Ambulatory Non-ambulatory Steroids during XRT No steroids Improved to N.F. I

Total

41 (48/l 18) 50 (3 1162) 30 (17156) 48 (43/90) 63 (30/48) 31 (13142) 18 (5/28) 7 (l/14) 29 (4/l4) 40 (34/85) 54 (23143) 26 (11142) 42 (l4/33) 42 (8/l9) 43 (6/l4)

71 (47166) 64 (23/36) 80 (24/30) 78 (719) 100 (3/3) 67 (4/6) 70 (40157) 61 (20133) 83 (20124) 76 (3I/4l) 67 (14121) 85 (17120) 64 (l6/25) 60 (9115) 70 (7/lO) 30 (20166) 22 (8/36) 40 (12130)

52 (951184) 55 (54/98) 48 (4l/86)

Note: No. of improvers/total patients are given in parantheses

of relief of headache with or without steroids were 85 and 89% respectively, and the corresponding rates of relief of motor loss were 67 and 68% respectively.

Table 7 presents mean times to progression by initial NF Class and by ambulatory status for the 242 patients with evaluable NF progression data. The treatment differences are not statistically significant.

Among the 214 evaluable patients who progressed or died, 100 (47%) died with neurologic function in an improved or unchanged state. Forty-nine of these patients died of known causes other than brain metastases. When these 49 cases are considered in the life table calculation as unrelapsed withdrawals at the time of death, the estimated median time to “local” progression is 14 weeks.

DISCUSSION

The present study confirms the already well-estab- lished effectiveness of brain irradiation in the palliation of symptoms resulting from intracranial metas- tases. ‘~2~5~6~7~8~9~‘o~“~‘3~‘4 It does not, however, substantiate

the hypothesis that a more aggressive treatment program provides any benefit beyond that attainable with a stan- dard short course, even for the selected population of favorable patients who were the subjects of this trial. On the contrary, for NFII patients the short treatment course resulted in a greater percentage of neurologic improvement than the higher dose course, and the previous larger RTOG studies suggested that symptom- atic improvement was more rapidly obtained with shorter treatment schedules.’ Also with the shorter course, retreatment of the brain was apparently viewed as a more realistic possibility when the need arose.

The small number of breast cancer patients in the study population, which was heavily weighted with lung cases, perhaps does not justify applying the above conclu- sions to the treatment of metastatic breast cancer, whose natural history is so different from that of bronchogenic carcinoma. Nonetheless, no trends were noted which would encourage one to suspect that any important treat- ment differences exist.

Despite the selection criteria, the median survival of

Table 6. Relief of specific symptoms by treatment

Symptom

3,000 rad/2 wks (130 patients)

Patients Symptom Completely presenting relieved relieved

# % %

5,000 rad/4 wks ( I25 patients)

Patients Symptom Completely presenting relieved relieved

# % %

Headache 85 66 (60) 88 82 Motor loss 72 51 (66) 62 52 Impaired mentation (49) 67 57

I;:; 53 48

Cerebellar symptoms (44) 77 57 59 51 Convulsions (16) 94 81 (17) 88 88 Cranial nerve involvement (22) 64 45 62 62 Nausea (26) 88 77 77 69

Note: No. of patients is given in parentheses.

Palliation of brain metastases 0 J. M. KURTZ et al. 895

Table 7. Estimated median time to progression (in weeks)

Rad/wks

Total

Total I I (214/242) Initial N.F. I I4 (54/70) Initial N.F. II 9(102/111) Initial N.F. Ill I3 (58/61) Ambulatory 1 I (140/163) Non-ambulatory IO (74/79)

Note: No. of failures/patients are given in parentheses.

3,000/2 5,000/4

1 I (109/124) 10(105/118) I2 (25132) I6 (29/38) IO (54/60) 9 (48/51) 9 (30/32) 14 (28/29)

I I (68/81) IO (72/82) IO (41/43) IO (33/36)

patients in this study (17 weeks) did not differ from the to benefit from more effective treatment of brain metas- median survival rates of patients in the first two unse- tases. Further studies investigating dose-fractionation lected RTOG studies (I 8 and 15 weeks).’ Only the subset schemes, high linear energy transfer (LET) radiation, of patients with breast or unknown primaries tended to radiosensitizers, and surgical excision should perhaps be have longer survival rates (47 weeks). For lung cancer directed at such patient populations. patients the selection criteria of this study do not appear Until progress should issue from such further studies, to define a prognostically favorable subpopulation. the treatment of choice for the great majority of patients

Since death is clinically attributable to uncontrolled with metastatic cancer to the brain remains a short one or brain metastases in more than half of treated patients two-week course of 2000-3000 rad. Compared to the regardless of treatment schedule, improvement in local longer fractionation schedules, such a brief course is control is a goal which remains to be achieved. Although completed by a larger percentage of patients, is at least as greater local control would most likely influence the effective in alleviating symptoms and controlling the median survival of lung cancer patients very little, favor- metastatic foci, and is more convenient and less costly to able subgroups of patients (e.g. single metastatic foci, the patient. The subpopulation of patients who might long disease-free interval) with less aggressive neoplasms benefit from more aggressive therapy remains to be (e.g. breast, large bowel, kidney) might still be expected defined.

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