COMPARISON OF THREE METHODS OF CENTRAL-NERVOUS-SYSTEM PROPHYLAXIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA

1398

Treatment of Malignant Disease

dard-risk patients. There were no significant differences in overall survival between the three groups of standardrisk patients. INTRODUCTION

COMPARISON OF THREE METHODS OF CENTRAL-NERVOUS-SYSTEM PROPHYLAXIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA ARNOLD I. FREEMAN

DANIEL M. GREEN

Departments of Pediatrics, Roswell Park Memorial Institute and State University of New York at Buffalo, Buffalo, New York

HARLAND N. SATHER

Department of Biostatistics, University of Southern California, Los Angeles, and Children’s Cancer Study Group, Los Angeles STEPHEN E. SALLAN

Department of Pediatric Oncology, Sidney Farber Cancer Institute; Department of Pediatrics, Harvard Medical School;

of Hematology/Oncology, Children’s Hospital Medical Center, Boston, Massuchusetts

and Division

MARK E.

NESBIT, JR Department of Pediatrics, University of Minnesota, and Children’s Cancer Study Group, Los Angeles J. ROBERT CASSADY Joint Center for Radiation Therapy, Boston, and Department of Radiation Therapy, Harvard Medical School, Boston LUCIUS F. SINKS Division of Pediatric Oncology, Vincent Lombardi Cancer Research Center, Georgetown University, Washington, D. C.

DENMAN HAMMOND

University of Southern California and Children’s Cancer Study Group, Los Angeles EMIL

FREI, III Sidney Farber Cancer Institute, Boston, and Department of Medicine, Harvard Medical School

retrospective comparison was made of three methods of central-nervous-system prophylaxis in childhood acute lymphoblastic leukæmia; (1) intrathecal methotrexate only; (2) intermediate-dose methotrexate infusion and intrathecal methotrexate and; (3) 2400 rads cranial irradiation and intrathecal methotrexate. The incidence of primary meningeal relapse was statistically significantly lower in both standard-risk patients (age >24 months and ≼120 months white-cell count <20 000) and increased-risk patients months or months and/or white-cell >120 (age ≼24 count >20 whose 000) central-nervous-system prophylaxis included cranial irradiation. The disease-free and overall survival of irradiated increased-risk patients was significantly better than that of unirradiated increasedrisk patients. The disease-free survival of standard-risk patients who received intermediate-dose methotrexate was statistically superior to that of the remaining stanSummary

A

THE central

system (CNS) was not recognised site of initial relapse in children and important adolescents with acute lymphoblastic leukxmia (ALL) until systemic maintenance programmes were developed which could provide such patients with long periods of bone-marrow remission.1-3 Early treatment of subclinical meningeal leukxmia ("prophylaxis") was introduced into management protocols because overt CNS leukxmia could not generally be treated successfully .4-6 Intrathecal methotrexate,7 craniospinal irradiation,8,9 and cranial irradiation plus intrathecal methotrexate8 were each shown to be effective in delaying or preventing primary meningeal relapses. The long-term deleterious effects of irradiation and chemotherapy on normal tissues are well known.11-13 Patients receiving CNS prophylaxis with cranial irradiation and intrathecal methotrexate and systemic maintenance treatment with modest doses of intravenous methotrexate had a much higher incidence of leukoencephalopathy than a concurrently treated group of p-atients who received similar CNS prophylaxis but lower doses of intravenous methotrexate in combination with daily oral 6-mercaptopurine.’14 One group of investigators reported a high frequency of intracranial abnormalities of unknown aetiology and clinical significance demonstrable with computed tomography of the head in patients who received prophylactic cranial irradiation and intrathecal chemotherapy. 15 Others have been unable to demonstrate a high frequency of such abnormalities in similarly treated children.16,17 These abnormalities were rare in patients with ALL who had not received prophylactic cranial irradiation.18 Reports about long-term intellectual function effects of prophylactic cranial irradiation are connervous

as an

flicting.19-21 This retrospective analysis compares three different methods of CNS prophylaxis in childhood ALL: (1) intrathecal methotrexate; (2) cranial irradiation and intrathecal methotrexate; and (3) intermediate-dose intramethotrexate and intrathecal methotrexate. Although the systemic maintenance chemotherapy programmes differed in the patient groups, prognostic factors such as age at diagnosis and presenting white-bloodcell count were controlled in this analysis. venous

PATIENTS AND METHODS

patients included in the present analysis were entered single-institution studies and one cooperative group study (see table). The treatment schemes are shown in fig. 1 and have been reported previously.22-24 The

on two

Between December, 1973, and December, 1976, 54 consecutive, previously untreated patients with ALL were entered on a pilot protocol at the Roswell Park Memorial Institute (RPMI ID-MTX). Patients presenting with an anterior-mediastinal

abdominal mass and bone-marrow involvement with were excluded. In June, 1976, entry to the study was closed to patients who were aged 24 months or >120 months or who had a presenting white-blood-cell count (WBC) >30 000/mm’. Patients were evaluated according to their mass or

lymphoma

status on

June 30, 1979.

1399 PATIENTS ENTERED ON THE THREE PROTOCOLS

bone-marrow remission, to the intrathecal-methotrexate-only arm of the study conducted by the Children’s Cancer Study Group (CCSG; protocol CCG-101). Patients aged under 18 months at diagnosis were non-randomly assigned to receive intrathecal methotrexate only during the sanctuary phase of treatment, and patients aged over 16 years at diagnosis were ineligible for entry to the study. Those patients who were randomised to receive intrathecal chemotherapy only during the sanctuary phase, and who remained in remission, were recalled in November, 1974, or May, 1975, and given additional central-nervous-system prophylaxis. Those patients who presented with a WBC <20 000/mm3 received cranial irradiation and intrathecal methotrexate, whereas those patients who presented with a WBC >20 000/mm received craniospinal irradiation. At the time of recall of 10 of the 79 patients (12.6%) had asymptomatic CNS leuksemia. For the purposes of this statistical analysis, all recalled patients were considered censored at the time of recall. Patients who did not have a chest X-ray at the time of diagnosis were excluded from this analysis. Patients were evaluated according to their status in August, 1979. Thus, the patients entered on the three ALL therapy trials were consecutive, previously untreated patients, aged 18 months to 16 years at diagnosis, who had achieved complete remission and who at diagnosis had neither overt meningeal leukxmia nor an anterior media-stinal mass. The exclusions were necessary because of the different treatment policies used by the three centres. Patients from all three studies were assigned a risk status, depending upon their age and WBC at diagnosis. Patients were defined as increased risk if they were aged 24 months or 120 months at diagnosis and/or presented with a WBC 20 000/mm3. The remaining patients were defined as standard risk. Within the risk categories, the distributions of patients by age, sex, and WBC were analysed with the chi-square test for homogeneity of proportions. 26 The time to first event (bone-marrow, CNS, or testicular relapse, or death in remission), time to primary CNS relapse, and time to death were analysed with life-table methods. The treatment regimens were compared in pairs with the MantelPeto-Cox summary chi-square statistic for life-table data .21 Differences were considered significant ifp<0-05.

*Prophylaxis randomised only after a patient achieved a complete remission. Thus, induction failures and deaths are not evaluable against randomised sanctuary treatment. tPatient with T-cell leukaemia withdrawn from study in remission. -

Between November, 1973, and

June, 1977, 137 consecutive,

previously untreated patients with ALL were treated at the Sidney Farber Cancer Institute (protocol SFCI 73-01). 3 patients with T-cell ALL25 who remained in their first remission were removed from study in November, 1976, and the study was closed to newly diagnosed patients with T-cell leukaemia. Patients were evaluated according to their status on June 30, 1979. Between July, 1972, and August, 1974, 143 previously untreated children with ALL were randomised, after achieving

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V,1 VINCRISTINE (15"’9/ni’ IV) (225mg/m2× 5DAYS, PO)

PREDNISONE (120mg/m2/DAY

IF AGE <6 YEARS,

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CRANIAL IRRADIATION = 2400 RADS /12 FRACTIONS

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CONTINUOUS INFUSION

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1-Treatment schemes.

Top: after 48

SFCI 73-01 (treatment is discontinued after 30 months of continuous remission). Middle: RPMI (ID MTX) (treatment is discontinued months of continuous remission). Bottom: CCG-101 (continuation of treatment is randomised after 36 months of continuous remission).

.

1400 RESULTS

For standard-risk patients there were no significant differences between the three groups in the distributions by sex or presenting WBC. There was a significant difference in the age distribution. The proportions of standard-risk patients over 84 months of age at diagnosis SFCI patients 33.3%, RPMI (ID MTX) 21.9%, and CCG-1018.7%. Among increased-risk patients, there were no significant differences in the distributions by sex, age at diagnosis, or WBC at diagnosis. were:

Disease-free Survival (Fig. 2) The disease-free survival of standard-risk patients entered on RPMI (ID MTX) was significantly better than that of patients entered on CCG-101 (p=0.003) or SFCI 73-01 (p=0.028). The difference between regimens CCG-101 and SFCI for standard-risk patients was not

statistically significant.

The disease-free survival of increased-risk patients entered on SFCI 73-01 was significantly better than that of patients entered on either RPMI (ID MTX) (p=0.012) or CCG-101 (p=0.025). The difference between RPMI (ID MTX) and CCG-101 for increasedrisk patients was not statistically significant.

Primary Meningeal Relapse (Fig. 3) Primary meningeal relapse was significantly less frequent among standard-risk patients entered on SFCI 73-01 than among those entered on either RPMI (ID MTX) (p=0.042) or CCG-101 (p=0.001). Primary meningeal relapse was significantly more frequent in

2

6

10

14

18

22

26

30

34

38

42

46

50

54

58

62

66

MONTHS not had a primary central-nervous-system relapse. A, standard-risk patients. B, increased-risk patients. Numbers in parenthesis are numbers of patients with more than 60 months of follow-up.

Fig. 3-Percentage

of patients who have -

standard-risk patients entered on CCG-101 than in patients on RPMI (ID MTX) (p=0.009). Among increased-risk patients primary meningeal relapse was significantly less frequent in patients entered on SFCI 73-01 than in those on either RPMI (ID MTX) or CCG-101 The difference (p<0.001) (p<0.001). between RPMI (ID MTX) and CCG-101 for increasedrisk patients was not statistically significant. Survival (Fig.

4)

The survival of standard-risk patients was significantly better for those entered on RPMI (ID MTX) than for those entered on CCG-101 (p=0.007). The survival of increased-risk patients was significantly better for those on SFCI 73-01 than for those on CCG-101 (p=0.023). Comparison of other pairs of treatment regimens showed no statistically significant differences for either standard-risk or increased-risk patients. MONTHS DISCUSSION

Z

t)

1V

14

18 22

Zb

30

34

38

42

48

50

54

58

62

64

MONTHS

Fig. 2—Disease-free survival of (A) standard-risk patients and (B) increased-risk patients. Vertical bars represent patients with less than 60 months of continuous remission; numbers in parenthesis are numbers of patients with more than 60 months of follow-up.

This study was undertaken to determine whether, when comparable groups of patients were analysed using specific criteria for the risk of relapse, an effect of prophylactic cranial irradiation on survival could be demonstrated. Although this study is neither a randomised nor a prospective trial, the three treatment protocols on which this analysis was based were conducted during the same period. The small number of deaths in remission suggests that toxicity of systemic chemotherapy did not contribute significantly to the differences which have been demonstrated. Two of the three treatment regimens were modified while the studies were in progress in both cases because of high rates of primary meningeal relapse. The RPMI study was closed to entry of increased-risk patients, so that few such patients were available for analysis. In the CCG-101 group the majority of patients initially

1401 or CCG-101 should not immediately be extended patients who have either an anterior mediastinal mass

73-01 to

lymphoblasts with T-cell antigens. The present analysis confirms the efficacy of prophylactic cranial irradiation in preventing primary meningeal relapse in patients with ALL. The importance of technical factors in such prophylaxis has been emphasised by Hustu et al,31and Dritschilo et al.32 Failure to include specific sites, such as the retro-orbital meninges, within the therapy portal may result in failure of control in some irradiated patients. The results of prophylactic cranial irradiation reported here demonstrate the efficacy of this modality when technical factors are rigorously controlled. Among standard-risk patients, as defined for this analysis, there were important differences in the incidence of primary meningeal relapse among irradiated and unirradiated patients. However, this analysis also suggested that the RPMI (ID MTX) protocol produced complete remission periods longer than those seen with SFCI 73-01 or CCG-101. The pharmacology of intrathecal33 and intravenous methotrexate,22 as used in the RPMI study, is such that the difference in the rate of primary CNS relapse between the CCSG and RPMI studies may be due either to delayed egress of methotrexate from the cerebrospinal fluid 22 or to the earlier initiation and longer duration of intrathecal therapy in the RPMI study.34 This question could be examined in a controlled trial. Among increased-risk patients, as defined for this analysis, the prevention of primary meningeal relapse through the use of prophylactic cranial irradiation and intrathecal methotrexate has resulted in statistically significantly longer disease-free and overall survival for the irradiated patients. The present results strongly suggest that prophylactic cranial irradiation administered shortly after bone-marrow remission is achieved should remain an integral component of management for many children with acute lymphoblastic leuksemia.

or

2

6

10

14

18

22

26

:0

34

38

42

46

50

54

58

62

66

70

74

MONTHS

Fig. 4-Overall survival of (A) standard-risk and (B) increasedrisk patients. Numbers in parenthesis are numbers of patients with more than 60 months offollow-up.

with intrathecal in remission received chemotherapy remaining supplementary prophylaxis to the central nervous system with cranial irradiation and intrathecal methotrexate or with craniospinal irradiation, depending on their WBC at diagnosis, late in the course of their treatment. Among standard-risk patients, the disease-free survival of those treated with RPMI (ID MTX) was significantly better than that of patients treated on either SFCI 73-01 or CCG-101. Although primarly meningeal relapse was significantly more common in both groups of unirradiated patients, the disease-free survival of the RPMI (ID MTX) patients was better than that of the irradiated patients. The disease-free survival of increased-risk patients on SFCI 73-01 was significantly better than that of such patients treated on RPMI (ID MTX) or CCG-101. Among the unirradiated increased-risk patients, the significantly higher rate of primary meningeal relapse was reflected in their lower rates of disease-free and overall survival. The difference in overall survival between patients’treated on SFCI 73-01 and CCG-101 was highly randomised

CNS only and

to

treatment

We thank the many physicians, nurses, and health professionals who cared for the patients included in this study, Ms Elena Greco for the illustrations, Mr Dan Terrana for the photography, and Ms Gerri Ziolkowski for secretarial assistance. This work was supported in part by grants CA 07306, CA 13539, CA 07918, CA 19589-03, CA 22719-01, and CA 17979-04 from the National Cancer Institute, National Institutes of Health, Department of Health, Education and Welfare.

Requests for reprints should be addressed to D. M. G., Department of Pediatrics, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N.Y. 14263, U.S.A. REFERENCES

significant. These results must be interpreted with caution, both because of the changes in treatment in two of the studies and because of the exclusions which were necessary to define a uniform patient population. Perhaps the most important group of excluded patients were those who presented with an anterior mediastinal mass. The majority of such patients have lymphoblasts with T-cell antigens. This subgroup has very aggressive disease and has a high incidence of primary extramedullary relapse.t4,2s-so The suggestion that, for children aged at least 24 months and under 120 months who have a WBC at diagnosis of less than 20 000/mm3, treatment which includes intermediate-dose methotrexate provides longer periods of complete remission than does SFCI

nervous system involvement in children with leukemia. Cancer 1964; 17: 256-58. 2. Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. Cancer 1970; 26: 404-09. 3. Hardisty RM, Norman PM: Meningeal leukæmia. Arch Dis Child 1967; 42: 441-47. 4. Gnbbin MA, Hardisty RM, Chessels JM. Long-term control of central nervous system leukæmia. Arch Dis Child 1977; 52: 673-78. 5. Hyman CB, Bogle JM, Brubaker CA, Williams K, Hammond D. Central nervous system involvement by leukemia in children: II. Therapy with intrathecal methotrexate. Blood 1965; 25: 13-22. 6. Sullivan MP, Vietti TJ, Fernbach DJ, Griffith KM, Haddy TB, Watkins WL. Clinical investigations in the treatment of meningeal leukemia: Radiation therapy regimens vs conventional intrathecal methotrexate. Blood 1969;

1. Evans

AE, Craig

M. Central

acute

34: 301-19. 7. Glidewell acute

OJ, Holland JF: Clinical trials of the lymphocytic leukemia in childhood.

1053-67.

leukemia group B in Bibl Hœmatol 1973; 39: acute

1402 HOLLYMOOR HOSPITAL DEMENTIA SERVICE’

.

Psychogeriatrics

one consultant took responsifor all referrals of dementia from July, 1976. One clinical assistant, one registrar, one community psychiatric nurse, one hospital-based social worker, and one part-time occupational therapist completed the team. Referrals come mainly from general practitioners. An admission ward with 4 male and 17 female beds is supported by 28 male and 62 female long-stay beds. There is no day hospital. There are no homes for the elderly mentally infirm. The majority of referrals are managed out of hospital. The community nurse looks after the patients and liaises with primary-care teams. The team social worker liaises with the local-authority services. At the outpatient clinic younger dements are investigated and some older patients are followed up. This paper describes the first 3 years of operation of the dementia service. By June, 1979, 230 referrals had been received.

At

Hollymoor Hospital

bility

HOLLYMOOR HOSPITAL DEMENTIA SERVICE

Analysis of Outcome of 230 Consecutive Referrals to a Psychiatric-hospital Dementia Service D. GASPAR

Hollymoor Hospital, Northfield, Birmingham B31

Summary

5EX

Among patients aged under 75 referred psychiatric-hospital dementia ser-

to a

vice the sex ratio was 1:1. In older age groups women greatly outnumbered men. More men than women were in need of institutional care, and mortality was significantly higher in men. Significantly more men than women were referred for aggressive behaviour, and significantly more women than men for paraphrenia-like symptoms. Prompt domiciliary assessment, neuroleptic treatment, and community help arranged by the dementia service enabled more than a third of patients referred to be managed at home. INTRODUCTION

proportion of old people in the population increases, so will the prevalence of dementia, and a service for demented patients is clearly becoming an essential part of the care of the elderly.1 Hollymoor Hospital Dementia Service, set up in July, 1976, received 230 As the

referrals in its first 3 years, and the referral

rate

is in-

creasing annually.

MANAGEMENT was based on prompt domiciliand followed the D.H.S.S. guidelines.2-a ary Patients with neither behavioural nor physical problems were referred to the social-services department (10 patients, 4.3%). Patients with physical problems were referred to geriatricians (45 patients, 19.6%). Those with behavioural problems (175 patients, 76-1%) were accepted as psychogeriatric responsibility. Patients with formidable problems were admitted immediately. Others (92 of 175) were managed at home. Where indicated, the psychiatrist administered a long-acting neuroleptic and left a supply of tablets. The community nurse took over

Management strategy assessment

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22. Freeman AI, Wang JJ, Sinks LF. High-dose methotrexate in acute lymphocytic leukemia. Cancer Treatment Rep 1977; 61: 727-31. 23. Robison L, Sather H, Coccia PF, Nesbit ME, Hammond D. Assessment of the interrelationship of prognostic factors in childhood acute lymphoblas-

mia. Br Med J 1973; ii: 381-84. 10. Crosley CJ, Rurke LB, Evans AE, and Nigro M. Central nervous system lesions in childhood leukæmia. Neurology (Minneap) 1978; 28: 678-85. 11. Meadows AT, Evans AE. Effects of chemotherapy on the central nervous

24. Sallan SE, Camitta BM, Cassady JR, Nathan DG, Frei E III. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: Clinical results. Blood 1978; 51: 425-33. 25. Scholssman SF, Chess L, Humpreys RE, Strominger JL. Distribution of Ialike molecules on the surface of normal and leukemia human cells. Proc Nat Acad Sci 1976; 73: 1288-92. 26. Dixon W, Massey F. Introduction to statistical analysis. New York: McGraw-Hill, 1969. 27. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and

system. Cancer 1976; 37: 1079-85. M, Krivit W, Heyn R, Sharp H. Acute and chronic effects of methotrexate on hepatic, pulmonary and skeletal systems. Cancer 1976; 37: 1048-54. 13. White DC. The histopathologic basis for functional decrements in late radiation injury in diverse organs. Cancer 1976; 37: 1126-43. 14. Aur RJA, Simone JV, Verzosa MS, et al. Childhood acute lymphocytic leukemia—Study VIII. Cancer 1978; 42: 2123-34. 15. Peylan-Ramu N, Poplack DG, Pizzo PA, Adornato BT, DiChiro G. Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. New Engl J Med 1978; 298: 12. Nesbit

815-18.

Day RE, Kingston J, Bullimore JA, Mott MG, Thomson JLG. CAT brain scans after central nervous system prophylaxis for acute lymphoblastic leukæmia. Br Med J 1978; ii: 1752-53. 17. Enzmann DR, Lane B. Enlargement of subarachnoid spaces and lateral ventricles in pediatric patients undergoing chemotherapy. J Pediatr 1978; 92: 16.

535-39. 18. Ochs J, Berger P, Brecher M, Sinks LF, Freeman AI. Computed tomography brain scans in children with acute lymphocytic leukemia (ALL) receiving methotrexate alone as central nervous system prophylaxis. Cancer 1980; 45: 2274-78. 19. Eiser C. Intellectual abilities among survivors of childhool leukemia as a

function of CNS irradiation. Arch Dis Child 1978, 53: 391-95. 20. Goff JR, Anderson HR, Powazek M, Marten GW. Distractability and memory deficits in long term survivors of acute lymphoblastic leukemia. Proc. Xth meeting Int Soc Pædiatr Oncol. 1978: 15. 21. Soni SS, Marten GW, Pitner SE, Duenas DA, Powazek M. Effects of central nervous system irradiation on neuropsychologic functioning of children with acute lymphocytic leukemia. N Engl J Med 1975; 293: 113-18.

tic leukemia. Am J Pediatr Hematol 1980; 2: 5-13.

examples. Br J Cancer 1977; 35: 1-39. 28.

Broject J, Valensi F, Daniel M, Flandrin G, Preud’homme J, Seligmann M. classification of tion of its clinical significance in

Immunological

acute a

lymphoblastic leukemias: Evaluapatients. Br J Hæmatol 1976;

hundred

33: 319-28. 29. Dow LW, Borella L, Sen L, et al. Initial prognostic factors and lymphoblast erythrocyte rosette formation in 109 children with acute lymphoblastic leukemia. Blood 1977; 50: 671-82. 30. Tsukomoto I, Wong KY, Lampkin BC. Surface markers and prognostic factors in acute lymphoblastic leukemia. N Engl J Med 1976; 294: 245-48. 31. Hustu HO, Aur RJA, Verzosa MS, Simone JV, Pinkel D. Prevention of central nervous system leukemia by irradiation. Cancer 1973; 32: 585-97. 32. Dristschilo A, Cassady JR, Camitta B, Jaffe N, Furman L, Traggis D. The role of irradiation in central nervous system treatment and prophylaxis for acute lymphoblastic leukemia. Cancer 1976; 37: 2729-35. 33. Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics.

Cancer Treatment Rep 1977; 61: 1419-25. 34. Sullivan MP, Humphrey GB, Vietti TJ, Haggard ME, Lee E: Superiority of conventional intrathecal methotrexate therapy with maintenance over intensive intrathecal methotrexate therapy, unmaintained or radiotherapy (2000-2500 rads tumor dose) in treatment for meningeal leukemia. Cancer 1975; 35: 1066-73.