Scand J Haematol (1979) 23, 119-123

Interhospital Differences in the Treatment of Acute Leukaemia in Adults

THE FINNISH LEUKAEMIA GROUP: Meilahti Hospital (lst, 2nd and 3rd Departments of Medicine), University Central

Hospital, Helsinki: E. Ikkala, chairman, R. Lahtinen, E. Niskanen, T. Ruutu &

P. Vuopio University Central Hospital, Kuopio: Auli Hanninen University Central Hospital, Oulu: I. Palva & T. Timonen Central Hospital, Tampere: Marja Lehtinen University Central Hospital, Turku: A. Levanto (t), A. Rajamaki & J. Vilpo Fourth Department of Medicine, University Central Hospital, Helsinki: 0. Selroos Central Hospital, Joensuu: Pia Ahrenberg Central Hospital, Kokkola, S. Rosengbrd Central Hospital, Lappeenranta: E. Waris Central Hospital, Vaasa: C. Wasastjerna 8r M. Saarni Kivela Hospital, Helsinki: C. Wasastjerna Department of Public Health Science, University of Helsinki: S. Sarna

During 5 years 203 adults with acute leukaemia were treated with a combination of daunorubicin, cytararabine and prednisone in the trials of the Finnish Leukaemia Group (FLG). The participating hospitals were classified according to size into 3 groups: 75 patients were treated in Meilahti Hospital (University Central Hospital, Helsinki), 87 patients - over 5 patients per year in each of the hospitals of the KOTT- group (university hospitals in Kuopio, Oulu, Tampere and Turku), and 41 patients - 1 to 3 patients per year in each of the 6 hospitals of the other hospital group. The remission rate in other hospitals (21 %) was significantly (P < 0.002) inferior to to those in Meilahti Hospital (54 %) and in the KO=-group (51 %). Evaluation of the survival data showed no difference between Meilahti Hospital and KOTT-group, but the survival in other hospitals was significantly poorer, differing from that of Meilahti (P = 0.01) and from that of KOTT-group (P = 0.02). The durations of re- missions did not differ from each other. The distribution of patients by the type of leukaemia was similar in all groups and the interhospital differences were not related to the type of leukaemia. The remission rates in other hospitals were in all age groups smaller than in the two other groups. The experience and skill gained by the doctors and the other hospital staff in treating more patients with acute leukaemia were regarded to be the main determinant of the better results achieved in the university hospitals. The slight differences in the age distribution of patients and in the facilities for supportive treatment were regarded to be of only minor importance.

Key words: acute leukaemia - centralizatio'n - treatment

Accepted for publication May 10, 1979

Correspondence to: Dr. E. Ikkala, M.D., 2nd Department of Medicine, University of Helsinki, 00290 Helsinki 29, Finland

0036-553X/79/070119-05 $02.50/0 @ 1979 Munksgaard, Copenhagen

120 THE FINNISH LEUKAEMIA GROUP

The main aim of the Finnish Leukaemia Group (FLG) has been to make the treat- ment of acute leukaemia in adults more uniform and to improve its results in Fin- land. The trials have covered about 70 % of adult patients with acute leukaemia in Finland. The remission rates of 35 % to 49 % (FLG 1974, 1979) compare well with other multicentre trials (Medical Research Council 1974, Southwest Oncology Group, Coltman et a1 1978). Higher remission rates with the same type of combinations of drugs have, however, been reported from single centres (Crowther et a1 1973, Paolino et a1 1973, Clarkson et a1 1975, Spiers et a1 1977). There seems to be a general impres- sion that the results of multicentre trials are inferior to those of specialized centres. Enck et a1 (1976) and Jacobs et a1 (1977) on the other hand, pointed out that the re- sults are better in large than in small hospi- tals. In these comparisons no uniform treat- ment protocol was followed.

A combination of daunorubicin, cytara- bine and prednisone (RAP) has been in- cluded in all the trials of the FLG during a 5-year period. The present paper records and analyses the results achieved with this protocol in different types of hospitals.

SERIES AND METHODS

All adult patients (over 15 years) admitted to the participating hospitals from Sept 1, 1971 to Aug 31, 1976 were included in trials 1-111 of the Fin- nish Leukaemia Group. Trials I and 111 consisted of a comparison of RAP treatment (daunorubicin, cytarabine and prednisone) with other combina- tions of drugs (FLG 1974, 1979). Trial I1 was an interim phase where all the patients were treated with RAP. In these 3 trials a total of 203 patients were treated with RAP regimen and these patients are the subject of the present report.

The participating hospitals are classified ac- cording to size into 3 groups:

Meilahti. lst, 2nd and 3rd Departments o'f Medi- cine in the University Central Hospital of Hel- sinki.

KOTT-group. Departments of Medicine in Uni- versity Cenrtal Hospitals of Kuopio (since Dec 1, 1973), Oulu, Tampere and Turku.

Other hospitals. 4th Department of Medicine, Uni- versity Central Hospital, Helsinki, Central Haspi- tals in Joensuu, Lappeenranta, Kokkola (since Dec 1, 7973) and Vaasa, and Kivela Hospital in Helsinki.

The diagnosis and classification of leukaemia were confirmed by a group of us as described earlier (FLG 1974, 1979).

The RAP regimen consisted of daunorubicin 60 mgJmZ i.v. on day 1, and cytarabine 80 mg/m2 i.v. and prednisone 50 mg/m2 orally, both daily on days 1-4. The courses were repeated at least 4 times with intervals of 10-14 d if a remission was not achieved earlier. The courses were with- held if bone marrow showed less than 5 % blast cells or severe hypocellularity with less than 25 % blast cells.

N o uniform isolation procedures were em- ployed, but in all hospitals most of the patients were treated in isolated rooms without air-filtra- tion facilities. Antibiotics were used for the treat- ment of infections whenever necessary. Granulo- cyte transfusions were used in Meilahti Hospital since 1975. For the treatment of bleedings freshly drawn blood was available in all centres and platelet concentrates in university hospitals. They were not used prophylactically.

The criteria of the Midwest Cooperative Chemotherapy Group (Hewlett et a1 1964) were used to evaluate the remissions. Complete and partial remissions are combined in this analysis.

After a remission had been achieved, a further course of RAP was given for consolidation in trial 111. The maintenance treatment in trial I was 6-mercaptopurine 90 mg/m2 per 0s daily; in trials I1 and 111, in addition to daily 6-mer- captopurine (70 mg/m*), oral methotrexate (12 mg/mz) was given once a week. In trial I11 the patients were also randomly allocated for treat- ment with or without Levamisole.

CENTRALIZATION IN ACUTE LEUKAEMIA 121

Number of patients with AML

totallwith remission

TABLE 1 The number of remissions in patients with acute myelogenous leukaemia (AML) and with

acute non-myelogenous (ANML} leukaemia in different hospital groups

Number of patients with ANML

total/with remission

~

Hospital group

~~

Meilahti KOIIT Other hospitals Total

59/29 (49 %) 71/31 (44 %) 3517 (20 %)

165167 (41 %)

16/12 (75 %) 16/13 (81 %) 6/2 (33 %)

38/27 (71 %)

TABLE 2 The number of remissions in different age groups by hospital groups

Number of patients, total/with remissions Age, years

Meilahti KOTT Other hospitals I ~ ~

< 30 22/17 (77 %) 15/11 (73 %) 7/3 (43 %)

50-65 21/10 (48 %) 24/10 (42 %) 10/2 (20 %) 30-49 18/11 (61 %) 27/15 (56 %) 12/2 (17 %)

> 65 1 4 3 (21 %) 21/8 (38 %) 12/2 (17 %)

RESULTS

Out of 203 patients 75 were treated in Meilahti Hospital, 87 in KOTT-group hos- pitals and 41 in other hospitals. The treat- ment with RAP regimen resulted in 36 re- missions in Meilahti Hospital, 38 in remis- sions in KOTT-group and 8 remissions in other hospitals. In the treatment of patients failing to respond with other combanations of drugs 5 remissions were achieved in Meilahti Hospital, 6 in KOTT-group and 1 in other hospitals. Thus the total number of remissions was 41 (54 %) in Meilahti Hospital, 44 (51 %) in KOTT-group and 9 (21 %) in other hospitals. The last figure differs from the two others significantly (P < 0.002 X2-test).

Table 1 shows the number of remissions

according to the type of leukaemia in the different hospitals. Acute lymphatic and acute leukaemia of undetermined type are combined under non-myelogeneous leukae- mia (ANML) and all other types under acute myelogeneous leukaemia (AML). Re- missions were obtained less frequently in AML than in ANML but the interhospital differences were not related to the type of leukaemia. The distribution of the subtypes of acute leukaemia was about the same in all hospital groups.

Table 2 shows the number of remissions in relation to the age of the patients. The remission rates in other hospitals were in all age groups smaller than those in the two university hospital groups. This differ- ence reached statistical significance at P < 0.05 level (X2-test) in age group 30-49

122 THE FINNISH LEUKAEMIA GROUP

years. 29 % of the patients treated in Meilahti were under 30 years while the corresponding figure for the 2 other hos- pital groups was 17 %.

The survival curves for patients treated in the different hospital groups are given in Figure 1. Evaluation of the survival data by

MElLAHTl H KOTT ib H OTHER HOSPITALS

38 patients was 11 %, whereas the remis- sion rates in patients with exact timing and with a delay of 1 to 7 d were 52 % and 56 %, respectively. The relative number of patients in this group was greatest in other hospitals: 24 % versus 13 % and 17 %. However, in other hospitals the remission rates in patients with exact timing (27 %) and a delay of 1 to 7 d (33 %) were clearly lower than the rates in the whole series.

DISCUSSION

1 o O d 6 ' 1 6 ' 2 4 ' 3 k 48 60 72 84 96 168 WEEKS

LENGTH OF SURVIVAL IN DIFFERENT HOSPITAL GROUPS

Figure 1. Survival of patients with acute leukae- mia in different hospitals in Finland from 1971- 1976.

the summary X2-test (Mantel 1966) showed no difference between Meilahti and KOTT- group but the survival in other hospitals was significantly poorer, differing from that in Meilahti (P = 0.01) and from that of KOTT-group (P = 0.02). The durations of remissions did not differ significantly from each other, however.

During the first 8 weeks, infection and haemorrhage or a combination of these were the main causes of death. Infection and haemorrhage were about equally com- mon. There were no interhospital differ- ences in this respect.

The treatment was discontinued in 3 pa- tients, and in 35 patients one or more of the scheduled courses were delayed by more than 7 d. The remission rate in these

Analysis of the results of the FLG from 1971-76 disclosed significant differences in the remission rates in different hospital groups although the protocol was the same in all. There were slight differences in the facilities for supportive treatment: platelet concentrates were available in all university hospitals and granulocyte concentrates in Meilahti Hospital from 1975. The age of the patients was somewhat more favourable in Meilahti Hospital, where the number of young patients was greatest. Although these circumstances might have a slight ef- fect on the results, they can hardly have any decisive effect on the differences ob- tained between different hospitals. In Meilahti Hospital about 15 patients

with acute leukaemia were treated every year. The corresponding number in each of the KOTT-group hospitals was over 5 , but in each of the other hospitals only 1 to 3. We feel that the experience and skill gained by the doctors and by the other hos- pital staff in treating more patients with leukaemia have been the main determinant of the better results achieved in the univer- sity hospitals.

Our results clearly warrant the recom- mendation that patients with acute leukae- mia should be referred to one of the 5 uni-

CENTRALIZATION IN ACUTE LEUKAEMIA 123

versity hospitals in Finland. This recom- mendation is further corroborated by the need of extensive facilities for supportive treatment in the high dose combination treatment which has been reported to re- sult in remission rates of over 80 % (Gale et a1 1977). In the preparation of these facilities a further restriction in the num- ber of hospitals treating patients with acute leukaemia may become necessary.

REFERENCES

Clarkson B D, Dowling M D, Gee T S, Cunning- ham I B & Burchenal J H (1975) Treatment of acute leukaemia in adults. Cancer 36 (Suppl) 775-95.

Coltman C A Jr, Bodey G P, Hewlett J S, Haut A, Bickers J, Balcerzak S P, Costanzi J J, Frei- reich E J, McGredie K B, Groppe C, Smith T L & Gehan E A (1978) Chemotherapy of acute leukaemia. A comparison of vincristine, cytara- bine and prednisone alone and in combination with cyclophosphamide or daunorubicin. Arch Intern Med 138, 1342-48.

Crowther D, Powles R L, Bateman C J T, Beard M E J, Gauchi C L, Wrigley P F M, Malpas J S, Hamilton Fairley G & Bodley Scott S R (1973) Management of adult acute myelogenous leukaemia. Br Med J i, 131-37.

Enck R E, Bauman A W & Bennett J M (1976) Adult acute leukemia. The Rochester (NY) ex- perience. Arch Intern Med 136, 1256-61.

Gale R P & Cline M J (1977) High remission- induction rate in acute myeldd leukaemia. Lan- cet i, 497-99.

Finnish Leukaemia Group (1974) Combination chemotherapy of acute leukaemia in adults. Comparison of two schedules. Scand J Haema- to1 12, 341-45.

Finnish Leukaemia Group (1979) The effect of thiaguanine on a combination of daunorubicin, cytarabine and prednisone in the treatment of acute leukaemia in adults. Scand J Haematol 23, 124-28.

Hewlett J S, Battle J D Jr, Bishop R C, Fowler W M, Schwartz S 0, Hagen P S & Louis J (1964) Phase 11 study of A-8103 (NSC-25154) in acute leukemia in adults. Cancer Chemother Rep 42, 25-28.

Jacobs A, Thompson E N & Whittaker J A (1977) Centres for leukaemic treatment. Lancet i, 1054.

Mantel N (1966) Evaluation of survival data and two now rank order statistics arising in its con- sideration. Cancer Chemother Rep 50, 163-70.

Medical Research Council’s Working Party on Leukaemia in Adults (1974) Treatment of acute myeloid leukaemia with daunorubicin, cytosine arabinoside, mercaptopurine, 1-asparaginase, prednisone and thioguanine: results of treat- ment with five multiple-drug schedules. Br J Haematol 27, 373-89.

Paolino W, Resegotti L, Rossi M & Infelise V (1973) Treatment of acute myeloid leukaemia according to the Hammersmith protocol: pre- liminary report. Br J Med iii, 567-68.

Spiers A S D, Goldman J M, Catovsky D, Costel- lo C, Galton D A G & Pitcher C S (1977) Pro- longed remission maintenance in acute myeloid leukaemia. Br Med J ii, 544-47.