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The effect of transfusions and antibiotics upon the duration of life in children with lymphogenous leucemia
T H E E F F E C T OF TRANSFUSIONS AND ANTIBIOTICS UPON T H E DURATION OF L I F E IN C H I L D R E N W I T H LYMPHOGENOUS LEUCEMIA HOWARD R .
COHEN, M.D.,~ JAMES N . M.A., PH.D.,$ AND MICHAEL B. S H I M K I N : M.D. ~ SAN FRANCISCO, CALIF.
BIERMAN, M . D . , "~ PETER
MCCLELLAND,
ECENT interest in chemotherapy for ]eucenlia in children has emphasized None of the therapeutic procedures thus far available change the ultimate final prognosis. On the other hand, temporary hematological and general clinical improvements are achieved in approximately one-third of the patients with the use of folic acid antagonists, and present results suggest that temporary ameliorative effects are also obtained with adrenocorticotrophic hormone and 17-hydroxy-]l-dehydrocorticosterone. The clinical impression is that these transient improvements are reflected in prolongation of life in children.with leucemia, although no conclusive information on this point exists in the literature. Moreover, the available data do not take into adequate consideration the fact that during the past decade blood transfusions, antibiotics, and other supportive measures have had an increasingly important role in the management of childhood ]eueemia. Since hemorrhage and intercurrent in%ction have been the two major immediate causes of death in leucemia in children, it is conceivable that some of the effects attributed to chemotherapeutic agents are at ]east in part due to supportive measures. This report deals with the duration of life in children with lymphogenous leucemia, and the influence of transfusions and of Penicillin and/or sulfonamides upon the course of the disease.
R the need for basic data on the natural history of the disease.
MATERIALS AND METHODS
A review was made of consecutive cases of leucemia in children under 15 years of age who ~vere admitted to the Pediatrics Service of the University of California Hospital during the period 1939 to 1948, inclusive. There were 103 cases of leucemia, of which 90 were classified as ]ymphogenous, 10 myelogenous, and 3 monoeytic in type (Fig. 1). Because of its prevalence in children, only the cases with ]ymphogenous leucemia were studied. Follow-up data were not available on 9 patients, and, for the statistical evaluation of survival, 5 additional patients were excluded, leaving a total of 76 cases. The five cases which were excluded from the analysis included the following: An accidental death due to puncture of a thymic blood vessel during a sternal marrow aspiration occurred in one child, four months after apparent *Laboratory of Experimental Oncology, National Cancer Institute, National Institutes of Health, and the University of California School of Medicine. ~Deloartment of Pediatrics, University of California School of Medicine. $Caneer Research Institute, University of California School of Medicine.
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onset of the disease; this patient had received no treatment. One patient had a Blalock operation for a congenital cardiac anomaly, and developed a leucemic blood picture eleven months later; she received no treatment and died one month later. The third patient was e x c l u d e d because of the presence of an arteriovenous aneurysm prior to the onset of leucemia. Two cases were excluded from the statistical analysis because of long survival which resulted in skewed distribution of the data. One of these patients was alive five years after the apparent onset of the disease. The other one died eighty-four months after the onset of lymphogenous leucemia as diagnosed r e p e a t e d l y on the basis of clinical and hematological criteria including bone m a r r o w aspirations; however, the final clinical diagnosis was aplastic anemia and necropsy was not performed. Both patients received blood transfusions and antibiotics. The exclusion of these five eases does not alter the conclusions of this r e p o r t and, in fact, their inclusion would f u r t h e r accentuate the differences in survival elicited by the present analysis. "TYPE LYMPHO GENOU,S MYE L OGENOU5
M ON OCYT I C Fig'. 1 . - - T y p e s
NUMBER OF CASES 10 P.O 3 0 4.0 50 "70 8 0 gO ~)~::~:}~))~)~)~)~)~::~:~:~)~::~:)~}~:~{~:~::~::~:~::~:~::~{~{~:.~:~::~.]9 0 i:i:i:i:i:i:i:i:i:i:!:~i110
ili315--
of l e u c e m i a in 103 c h i l d r e n a d m i t t e d to t h e U n i v e r s i t y 1939 t o 1948.
of C a l i f o r n i a
Hospital,
The duration of disease was determined from the time of appearance of the first m a j o r signs and symptoms to the time of death. The onset of leuccmia is usually insidious and a d m i t t e d l y difficult to determine exactly. I t was recorded as accurately as possible, however. Clinical manifestations attributable to subsequently established diagnosis of lymphogenous leueemia included m a r k e d l y m p h a d e n o p a t h y , progressive severe anemia, hemorrhagic diathesis, severe bone and joint pain, and enlargement of the liver and spleen. The diagnosis of leucemia was made by the usual clinical and hematological criteria, including in each ease an examination of the bone marrow. The eases were divided into four groups: (1) Eighteen cases received no t r e a t m e n t with irradiation, blood transfusions, penicillin, or sulfonamides; (2) patients who received irradiation treatment, either b y x - r a y or radiophosphorus/ Most of this group of 17 cases also received blood transfusions and penicillin or sulfonamides at some time during the course of the disease; (3) 24 eases received blood transfusions during their illness, but no antibiotics; (4) patients who were treated with both blood transfusions and penicillin a n d / o r sulfonamides. Penicillin was given i n t r a m u s c u l a r l y for periods up to t h i r t y days although in most instances it was discontinued within one week. Sulfonamides were given orally in usual doses for periods not exceeding two weeks. There was a total of 17 eases in this category. Iron, vitamins, and liver preparations w e r e administered to many of the patients in all four groups, b u t exact data sufficient for p r o p e r evaluation were not available.
BIERMAN
E T AL. :
LYMPHOGENOUS
LEUCEMIA
~7
RESULTS
O~ all 90 cases of lymphogenous ]eueemia, 56 were males and 34 were females. Peaks in incidence occurred at the age o~ 2 and o~ 4 years, with a range ~rom 3 months to 14 years (Pig. 2). The average age at onset was 5.0 years. The duration o~ survival in patients os different ages at onset is given in Fig. 3. Statistical analysis of these data show a slight, but not statistically significant, tendency s duration o~ survival to increase with age at onset. ~YmS.) AGEAT ONSET
NUMBER ~
~
6
OF B
lO
CASES
12
Fig. 2 . - - A g e a t w h i c h 90 c h i l d r e n f i r s t e x h i b i t e d m a j o r
AVERAGE. 1
~
SURVIVAL :5
4.
"~
1~-
1@
symptoms TIME 6
IN 7
18
~0
of l y m p h o g e n o u s
leucemia.
MONTH3 I~
~
10
14
13
o
,,
~ i{i{{iii:i{i!i{i:i{iiii{ii{i
,o
a ii~ii~iiiii!~iiii2i
914
!ii~il;i;:~i~ii:i~;:~i;ii:
,, 1~ ;ii!iiiiii::ii?iiiiiiiii!iiiii::ii 2 I+ I~iii~ii?iiiii~i TOTAL"~ Fig. 3.--Average
duration
of s u r v i v a l
of 76 c h i l d r e n w i t h to a g e a t o n s e t .
lymphogenous
leucemia,
according
The d u r a t i o n of survival was obtained in 76 patients (Table I ) , The average time of survival a~+ 18 eases who received no t r e a t m e n t was,,5.6 months, with a range of 2 to 16 months. Three cases (17 per cent) lived beyond 9 months.
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PEDIATRICS
])URATION OF SURVIVAL OF .76 CHILDREN WITH LYMPItOGENOUS LEUCEMIA THEI~APY
SURVIVAL TIME (I~[ONTHS)
NO TREATMENT
X-RAY
BLOOD O N L Y
BLOOD AND PENICILLIN AND/0tr SULFONAMIDES
0 2 0 0 1 2 2 7 4 18.0 5.6 4.0 0.9
0 0 0 2 2 2 2 9 0 17.0 5.8 2.7 0.6
0 0 0 0 6 5 6 5 2 24.0 6.0 2.4 0.5
1 0 2 2 4 2 3 3 0 17.0 8.9 4.8 1.2
4.4
6.2
5.0
4.6
Over 16 15-16 13-14 11-12 9-10 7-8 5-6 3-4 1-2 Total Average s Standard Deviation~ S t a n d a r d E r r o r of Mean* M e a n A g e a t Onset (years) *Values
obtained
from
raw
data
and
not from
data
as grouped
in Table.
Seventeen patients who received x-ray treatment and supportive therapy of blood and antibiotics at some time during the course of the disease had an average survival time of 5.8 months, with a range from 3 to 11 months. ~Four of these patients (23 per cent) lived beyond 9 months. Twenty-four patients who received blood transfusions, at some time during their illness, but no antibiotics, survived for an average of 6.0 months, with a range of 2 to 9 months. Six eases (25 per cent) survived 9 months or longer. Seventeen patients who received blood transfusions and penicillin and/or sulfonamides survived an average of 8.9 months, with a range of 3 to 23 months. Nine cases (53 per cent) in this category survived 9 to 23 months. It should also be emphasized that 17 to 25 per cent of the eases in the first three groups survived 9 months or longer. This makes it clear that claims for any therapeutic measures cannot be based on individual cases because of the considerable likelihood that these individuals would have had long" survival times even without supportive therapy. Statistical analysis of these four groups shows that there are no significant differences between the first three groups of patients. It may be concluded that irradiation therapy, or treatment by transfusions alone, have not been demonstrated to have a significant effect upon the duration of survival in children with lymphogenons leucemia. However, the mean survival period of the group of 17 patients who were treated with transfusions and penicillin a n d / o r sulfonamides was 8.9 months, as compared with the means of 5.6, 5.8, and 6.0 months in the other three groups. This mean survival time is significantly greater (P ~ 0.03) than the mean survival time of patients in any of the other three groups. Two eases of long" survival, one of whom died at 84 months and the othgr alive sixty months after apparent onset, were excluded from the analysis. Both of these patients were treated with transfusions and antibiotics. I f these.two eases were included, the difference between the group treated with antibiotics and transfusions and all
BIERICIAN ET AL. :
459
LYIVLPHOGENOUS L E U C E M I A
other groups would be even more significant. Furthermore, the average age at which onset of the disease was noted in the group is slightly lower than the average for the other three groups (4.6 years vs. 5.2 years) and, hence, age cannot be considered as a contributing factor in the increased survival times of the patients treated with transfusions and antibiotics (Figs. 2 and 3). I t may be concluded with a reasonable degree of certainty that the addition of penicillin and sulfonamides and transfusions to the treatment of children with lymphogenous ]eucemia was associated with an increased time of survival in this series. DISCUSSION
Chronic leucemias are rare in children. 1 Occasional reports of chronic myelogenous leucemia in children have appeared, Steinbrink, 2 Malmberg, 8 Esp, ~ but only a few cases of chronic ]ynlphogenous leucemia in, this age group have ever been authenticated. ~-s The designation of an acute or chronic leucemia is retrospective and dependent in p a r t upon the severity and the duration of the illness. Many cases exhibit a subacute course intermediate between that of acute or chronic leueemia. I n order to avoid a controversy, insoluble at present, the simple designation of lymphogenous leucemia in children was employed. The literature on leucemia in childhood contains several extensive series with data on the incidence, sex distribution, and duration of illness. Cooke, 6 Booth and Rembolt, 1~ Falkenstein and Fowler, ~1 Sullivan, Rice, and Cassidy, 1~ and Dale ~3 summarized data on 282 patients under 14 years of age with ]eucemia, of which 62 per cent were males. The average duration of survival in 252 cases, as measured from the onset of symptoms, was from 3.6 to 5.5 months. The results of Dale ~3 on 38 cases are in almost exact agreement with the presently reported data on children who were not treated, or were treated with transfusions or irradiation. The data combine lymphogenous and myelogenous leucemia (Table I I ) . TABLE I I .
DUI%ATtON OF SURVIVAL IN CHILDREN W I T H LEUCEMIA DURATION
AUTHOR Cooke G B o o t h a n d R e m b o l t 10 Falkensteln and Fowler11 S u l l i v a n e t a112 Dalel3 *Excluding
SOURCE OF . DATE DATES Missouri 1918-1933 Minnesota 1930-1938 Iowa to 1943 Dist. Columbia 1938-1947 1Vew Y o r k 1932-]948
1 c a s e of 34 m o n t h s '
CASES (No.) 50 40 61 63 38 ~
..
AVERAGE (MO~T~S) (MONTHS) SPREAD
0.5-9 0.1-7 0.5-14 0.5-15 0.5-20
.
3.6 4.2 4.3 4.0 5.5
duration.
There is but scanty information in the literature regarding tile influence of supportive treatment on tile course of childhood leucemia and on the length of survival. Most hematologists have seen at least a few instances of transient beneficial effect of blood transfusions on children with acute lymphatic ]eucemia. Schwind 14 observed that infusion of blood plasma was followed by a decrease in the percentage of myeloblasts in the blood. Dreyfus1 ~ has stated that the probability of a remission is related to the number of blood transfusions and the total
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amount of blood infused. Replacement transfusions have also been followed by remissions.16, ~7 On the other hand, Cooke ~ concluded that the effect of transfusions is transient and of questionable value. Palkenstein and F o M e r xl similarly reported that transfusions were given to thirty-four patients, and an analysis of the data revealed no evidence that the administration of blood prolonged the life of the patients. Sullivan and collaborators ~ stated that blood transfusion is the only measure that prolongs life appreciably, but gave no statistical data to support this contention. The present data agree with the conclusions of Cooke G and of Falkenstein and F o M e r ~ in that the group of children who received treatment with irradiation or with blood transfusions alone survived no longer than patients who received no treatment. I t must be realized, however, that the transfusions were given intermittently and not in massive amounts. ~00-
t
~
i 5 0 -
100-
50-
)
5
~
_
O 0 5 "tO DIFFI~I~ENCE B E T W E E N MEAN5 TWO GROUP5 (MONTHS)
OF
Assur~pt ion~ 1, N I = N g . 5 . G r o u p s identical i n a.]l r e s p e c t s therapy.
excepl;
F i g . 4 , - - N u m b e r of e a s e s n e e d e d to d e m o n s t r a t e d i f f e r e n c e s b e t w e e n two t h e r a p e u t i c m e t h o d s in t h e t r e a t m e n t of c h i l d r e n w i t h l y m p h o g e n o u s l e u c e m i a w i t h 50 p e r cent c e r t a i n t y .
In contrast, patients who received treatment with penicillin a n d / o r sulfonamides and with repeated transfusions showed a significant prolongation of life. F r o m these data alone it is of course not possible to determine whether this increase in survival time is the result of some specific actions of the antibiotics and ,blood transfusions against the leucemic manifestations or whether such t h e r a p y exerts its effects merely by improving the genera] condition of the patient and l~y controlling intercurrent infections. , : The employment of penicillin, sulfonamides, and other antibiotic agents have aborted and controlled m a n y infections which f r e q u e n t l y have been the
B I E R M A N ET AL. :
LYMPHOGENOUS
LEUCEMiA
461
9t e r m i n a t i n g event in patients with an acute leueemia. In addition, there have been reports of the coagulant p r o p e r t y of the antibiotics, is but they lack confirmation. 19 I f the antibiotics indeed diminish the hemorrhagic tendency in patients with acute ]eueemia, it would indicate a possible favorable effect of these agents in this group of diseases other than of a purely antibacterial nature. One must also consider the chemotherapeutic effect of antibiotic agents on as yet undiscovered infectious agents possibly related etiologically to leucemiaJ Statistical analysis of final results on sufficient numbers of adequately controlled cases is the only method by which prolongation of life or other effects of t h e r a p y can be acceptably, substantiated. This involves comparison of groups of treated patients with similar groups of " u n t r e a t e d controls," or at ]east with groups treated by some other method but similar in regard to sex, age, stage of disease, a n d general condition. The presently reported groups of children with ]eucemia a p p e a r to fu]fill the requirement of coming f r o m the same population. The data also allow statistical estimations of the n u m b e r of cases which would be needed in order to demonstrate differences between the effects of various forms of t r e a t m e n t in childhood leucemia. These calculations are given in Fig. 4. Assuming t h a t the untreated control group of another investigation shows the same mean survival and s t a n d a r d deviation, thirty-seven cases which are treated by a p a r t i c u l a r agent and survive on the average three months longer are necessary, for a conclusion that is statistically significant at the 1 per cent level (P = 0.01), 50 per cent of the time. To be more certain of attaining results significant at the 1 per cent level, a larger n u m b e r of cases would be needed. F o r example, for 95 per cent certainty at the 1 per cent level with a difference of three months between the means of the two groups, the number of cases needed in control and experimental groups rises to 100. The statistical method, therefore, is not only essential in the final evaluation of the data but is as necessary in the formulation of an experimental study in which conclusive results are desired. Evaluation of the t r e a t m e n t of leucemia in children requires an adequate control series of cases. I n clinical therapeutic investigations, it is usual to give supportive t h e r a p y r a t h e r t h a n to withhold t r e a t m e n t of a n y kind. Therefore, the effects of such t h e r a p y must be considered. Heretofore, such supportive t h e r a p y has been considered to have relatively little or no effect on duration of survival. T h a t some folie acid antagonists and other agents produce marked hematological changes in m a n y patients with acute leucemia cannot be denied. 2~ Clinical investigations with these agents hav e proceeded to the point where prolongation of life m a y be used to evaluate their efficacy. The influence of blood transfusions, antibiotics, and antihemorrhagic agents in the clinical management of children with leucemia who also receive such new agents must be considered before the chemical agents alone can be held responsible for the prolongation of life. SUMMARY
1. Ninety cases of lymphogenous leucemia in children under 14 years of age were studied, of which 76 were analyzed relative to duration of survival.
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THE JOURNAL OF PEDIATRICS
2. The average duration of survival of 18 eases of untreated lymphogenous leueemia in children was 5.6 months. 3. A group of 17 children who were treated with irradiation (x-ray or radiophosphorus) plus blood transfusions and antibiotics survived 5.8 months. 4. Twenty-four patients received blood transfusions but no penicillin or sulfonamide t h e r a p y and survived an average of 6.0 months. 5. Seventeen patients who received blood transfusions and antibiotics survived an average of 8.9 months, a significantly prolonged survival time in comparison with the first three groups. 6. The necessity of statistical comparison of patients treated experimentally by chemotherapeutic agents with an adequately controlled comparable group is emphasized. REFERENCES 1. Forkner, C . E . : Leukemia and Allied Disorders, New York, 1988, The Macmillan Co. 2. S t e i n b r i n k , W.: Beitrgge zur Pathologie der B l u t k r a n k h e i t e n , Deutsche reed. Wchnschr. 51: 106-108, 1925. 3. 3/[almberg, hr.: B e i t r a g zur X e n n t n i s der 1Vfyeloiden Leukgmie bei S~nglingen, Aeta Paediat. 4: 410-435, 1925. 4. Esp, E.: Chronische aleukaemische myeloisehe Leuk~mie bei einem 8 jg~hrigen X n a b e , Acta Paediat. 9: 89-117, 1929. 5. Bruin, 3//7. De: Chronlsehe lymphatische Leuki~mie in I(indesalter, Folia t I a e m a t . 48: 433-442, 1932. 6. Cooke, J. V.: Acute Leukemia in Children, J. A. M. A. 101" 432-435, 1933. 7. CoOke, J. V'.. The Incidence of Acute L e u k e m i a in Children, J. A. 3/[. A. 119: 547-550, 1942. 8. Gittins, R.: Studies in the Anemias of I n f a n c y and E a r l y Childhood, V I I I , Leukaemia (leucosis) in Children, Arch. Dis. Childhood 8: 291-322, 1933. 9. Holowach, J.: Chronic Lymphoid Leucemia in Children, J. P~DIAT. 32: 84-86, 1948. 10. Booth, 1VL, and Rembolt, /r R.: Leukemia in Childhood, L a n c e t 59: 216-229, 1939. 11. Falkensteinl D., and Fowler, W . M . : Acute L e u k e m i a in Childhood, Am. J. Dis. Child. 65: 445-454, 1943. 12. Sullivan, R. B., Rice, E. C., and Cassidy, J. E.: Leukemia. A Review of Sixty-Five Cases, Clin. Proc. Child. Hosp., Washington, D. C. 4: 195-207, 1948. 13. Dale, J. If., Jr.: Leucemia in Childhood, J. PEDIAT. 34: 421-432, 1949. 14. Sehwind, J . L . : P a r t i a l lVfaturation of Leukemic Myeloblasts Following F r e s h Plasma Transfusion, Am. J. 1Yr. Sc. 213: 170-175, 1947. 15. Dreyfus, R.: Le r ~ m i s s i o n s d e la leucgmic aigu~, Sang 19: 35-40, 1948. 16. Piney, A.: E x sanguino Transfusion in Acute Leukemia, L a n c e t 2: 379, 1948. 17. Bessis, M.: The Use of Replacement Transfusion in Diseases Other Than ttemolytic Disease of the Newborn, Blood 6: 424-437, 1949. 18. Editorial: A n t i b i o t i c s and Blood Coagulation, J. A. M. A. 141: 924, 1949. 19. Dolkart~ R. E., tIa]pern, B., Larkin, 3/f.~ Day, F. L., and deTakats, G.: The Effect of Penicillin Upon the Clotting A c t i v i t y of Blood in Normal H u m a n Subjects, J. Pharmacol. & Exper. Therap. 96: 291, 1949. 20. F a t h e r , S., Diamond, L. K., Mercer, E. D., Sylvester, R. F., and Wolfe, & A.: Temporary Remissions in Acute Leukemia in Children Produced b y Folio Acid Antagonist, 4-Aminopteroyl Glutamic Acid ( A m i n o p t e r i n ) , New E n g l a n d J. Med. 238: 787-793, 1948. 21. Stickney, J. M., Mills, S. D., tIagedorn, A. B., and Cooper, T.: The T r e a t m e n t of Acute Leukemia W i t h Folic Acid Antagonists, Proc. Staff Meet., Mayo Clinic 24: 525-533, 1949. 22. Weber, E. J., Iiarpinski~ F. E., Jr., and tIeinle, R. W.: The T r e a t m e n t of Acute Leukemias of Childhood W i t h Folic Aeld Antagonists, J. PEI)IAT. 36: 69-78, 1950.
COHEN, M.D.,~ JAMES N . M.A., PH.D.,$ AND MICHAEL B. S H I M K I N : M.D. ~ SAN FRANCISCO, CALIF.
BIERMAN, M . D . , "~ PETER
MCCLELLAND,
ECENT interest in chemotherapy for ]eucenlia in children has emphasized None of the therapeutic procedures thus far available change the ultimate final prognosis. On the other hand, temporary hematological and general clinical improvements are achieved in approximately one-third of the patients with the use of folic acid antagonists, and present results suggest that temporary ameliorative effects are also obtained with adrenocorticotrophic hormone and 17-hydroxy-]l-dehydrocorticosterone. The clinical impression is that these transient improvements are reflected in prolongation of life in children.with leucemia, although no conclusive information on this point exists in the literature. Moreover, the available data do not take into adequate consideration the fact that during the past decade blood transfusions, antibiotics, and other supportive measures have had an increasingly important role in the management of childhood ]eueemia. Since hemorrhage and intercurrent in%ction have been the two major immediate causes of death in leucemia in children, it is conceivable that some of the effects attributed to chemotherapeutic agents are at ]east in part due to supportive measures. This report deals with the duration of life in children with lymphogenous leucemia, and the influence of transfusions and of Penicillin and/or sulfonamides upon the course of the disease.
R the need for basic data on the natural history of the disease.
MATERIALS AND METHODS
A review was made of consecutive cases of leucemia in children under 15 years of age who ~vere admitted to the Pediatrics Service of the University of California Hospital during the period 1939 to 1948, inclusive. There were 103 cases of leucemia, of which 90 were classified as ]ymphogenous, 10 myelogenous, and 3 monoeytic in type (Fig. 1). Because of its prevalence in children, only the cases with ]ymphogenous leucemia were studied. Follow-up data were not available on 9 patients, and, for the statistical evaluation of survival, 5 additional patients were excluded, leaving a total of 76 cases. The five cases which were excluded from the analysis included the following: An accidental death due to puncture of a thymic blood vessel during a sternal marrow aspiration occurred in one child, four months after apparent *Laboratory of Experimental Oncology, National Cancer Institute, National Institutes of Health, and the University of California School of Medicine. ~Deloartment of Pediatrics, University of California School of Medicine. $Caneer Research Institute, University of California School of Medicine.
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onset of the disease; this patient had received no treatment. One patient had a Blalock operation for a congenital cardiac anomaly, and developed a leucemic blood picture eleven months later; she received no treatment and died one month later. The third patient was e x c l u d e d because of the presence of an arteriovenous aneurysm prior to the onset of leucemia. Two cases were excluded from the statistical analysis because of long survival which resulted in skewed distribution of the data. One of these patients was alive five years after the apparent onset of the disease. The other one died eighty-four months after the onset of lymphogenous leucemia as diagnosed r e p e a t e d l y on the basis of clinical and hematological criteria including bone m a r r o w aspirations; however, the final clinical diagnosis was aplastic anemia and necropsy was not performed. Both patients received blood transfusions and antibiotics. The exclusion of these five eases does not alter the conclusions of this r e p o r t and, in fact, their inclusion would f u r t h e r accentuate the differences in survival elicited by the present analysis. "TYPE LYMPHO GENOU,S MYE L OGENOU5
M ON OCYT I C Fig'. 1 . - - T y p e s
NUMBER OF CASES 10 P.O 3 0 4.0 50 "70 8 0 gO ~)~::~:}~))~)~)~)~)~::~:~:~)~::~:)~}~:~{~:~::~::~:~::~:~::~{~{~:.~:~::~.]9 0 i:i:i:i:i:i:i:i:i:i:!:~i110
ili315--
of l e u c e m i a in 103 c h i l d r e n a d m i t t e d to t h e U n i v e r s i t y 1939 t o 1948.
of C a l i f o r n i a
Hospital,
The duration of disease was determined from the time of appearance of the first m a j o r signs and symptoms to the time of death. The onset of leuccmia is usually insidious and a d m i t t e d l y difficult to determine exactly. I t was recorded as accurately as possible, however. Clinical manifestations attributable to subsequently established diagnosis of lymphogenous leueemia included m a r k e d l y m p h a d e n o p a t h y , progressive severe anemia, hemorrhagic diathesis, severe bone and joint pain, and enlargement of the liver and spleen. The diagnosis of leucemia was made by the usual clinical and hematological criteria, including in each ease an examination of the bone marrow. The eases were divided into four groups: (1) Eighteen cases received no t r e a t m e n t with irradiation, blood transfusions, penicillin, or sulfonamides; (2) patients who received irradiation treatment, either b y x - r a y or radiophosphorus/ Most of this group of 17 cases also received blood transfusions and penicillin or sulfonamides at some time during the course of the disease; (3) 24 eases received blood transfusions during their illness, but no antibiotics; (4) patients who were treated with both blood transfusions and penicillin a n d / o r sulfonamides. Penicillin was given i n t r a m u s c u l a r l y for periods up to t h i r t y days although in most instances it was discontinued within one week. Sulfonamides were given orally in usual doses for periods not exceeding two weeks. There was a total of 17 eases in this category. Iron, vitamins, and liver preparations w e r e administered to many of the patients in all four groups, b u t exact data sufficient for p r o p e r evaluation were not available.
BIERMAN
E T AL. :
LYMPHOGENOUS
LEUCEMIA
~7
RESULTS
O~ all 90 cases of lymphogenous ]eueemia, 56 were males and 34 were females. Peaks in incidence occurred at the age o~ 2 and o~ 4 years, with a range ~rom 3 months to 14 years (Pig. 2). The average age at onset was 5.0 years. The duration o~ survival in patients os different ages at onset is given in Fig. 3. Statistical analysis of these data show a slight, but not statistically significant, tendency s duration o~ survival to increase with age at onset. ~YmS.) AGEAT ONSET
NUMBER ~
~
6
OF B
lO
CASES
12
Fig. 2 . - - A g e a t w h i c h 90 c h i l d r e n f i r s t e x h i b i t e d m a j o r
AVERAGE. 1
~
SURVIVAL :5
4.
"~
1~-
1@
symptoms TIME 6
IN 7
18
~0
of l y m p h o g e n o u s
leucemia.
MONTH3 I~
~
10
14
13
o
,,
~ i{i{{iii:i{i!i{i:i{iiii{ii{i
,o
a ii~ii~iiiii!~iiii2i
914
!ii~il;i;:~i~ii:i~;:~i;ii:
,, 1~ ;ii!iiiiii::ii?iiiiiiiii!iiiii::ii 2 I+ I~iii~ii?iiiii~i TOTAL"~ Fig. 3.--Average
duration
of s u r v i v a l
of 76 c h i l d r e n w i t h to a g e a t o n s e t .
lymphogenous
leucemia,
according
The d u r a t i o n of survival was obtained in 76 patients (Table I ) , The average time of survival a~+ 18 eases who received no t r e a t m e n t was,,5.6 months, with a range of 2 to 16 months. Three cases (17 per cent) lived beyond 9 months.
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])URATION OF SURVIVAL OF .76 CHILDREN WITH LYMPItOGENOUS LEUCEMIA THEI~APY
SURVIVAL TIME (I~[ONTHS)
NO TREATMENT
X-RAY
BLOOD O N L Y
BLOOD AND PENICILLIN AND/0tr SULFONAMIDES
0 2 0 0 1 2 2 7 4 18.0 5.6 4.0 0.9
0 0 0 2 2 2 2 9 0 17.0 5.8 2.7 0.6
0 0 0 0 6 5 6 5 2 24.0 6.0 2.4 0.5
1 0 2 2 4 2 3 3 0 17.0 8.9 4.8 1.2
4.4
6.2
5.0
4.6
Over 16 15-16 13-14 11-12 9-10 7-8 5-6 3-4 1-2 Total Average s Standard Deviation~ S t a n d a r d E r r o r of Mean* M e a n A g e a t Onset (years) *Values
obtained
from
raw
data
and
not from
data
as grouped
in Table.
Seventeen patients who received x-ray treatment and supportive therapy of blood and antibiotics at some time during the course of the disease had an average survival time of 5.8 months, with a range from 3 to 11 months. ~Four of these patients (23 per cent) lived beyond 9 months. Twenty-four patients who received blood transfusions, at some time during their illness, but no antibiotics, survived for an average of 6.0 months, with a range of 2 to 9 months. Six eases (25 per cent) survived 9 months or longer. Seventeen patients who received blood transfusions and penicillin and/or sulfonamides survived an average of 8.9 months, with a range of 3 to 23 months. Nine cases (53 per cent) in this category survived 9 to 23 months. It should also be emphasized that 17 to 25 per cent of the eases in the first three groups survived 9 months or longer. This makes it clear that claims for any therapeutic measures cannot be based on individual cases because of the considerable likelihood that these individuals would have had long" survival times even without supportive therapy. Statistical analysis of these four groups shows that there are no significant differences between the first three groups of patients. It may be concluded that irradiation therapy, or treatment by transfusions alone, have not been demonstrated to have a significant effect upon the duration of survival in children with lymphogenons leucemia. However, the mean survival period of the group of 17 patients who were treated with transfusions and penicillin a n d / o r sulfonamides was 8.9 months, as compared with the means of 5.6, 5.8, and 6.0 months in the other three groups. This mean survival time is significantly greater (P ~ 0.03) than the mean survival time of patients in any of the other three groups. Two eases of long" survival, one of whom died at 84 months and the othgr alive sixty months after apparent onset, were excluded from the analysis. Both of these patients were treated with transfusions and antibiotics. I f these.two eases were included, the difference between the group treated with antibiotics and transfusions and all
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459
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other groups would be even more significant. Furthermore, the average age at which onset of the disease was noted in the group is slightly lower than the average for the other three groups (4.6 years vs. 5.2 years) and, hence, age cannot be considered as a contributing factor in the increased survival times of the patients treated with transfusions and antibiotics (Figs. 2 and 3). I t may be concluded with a reasonable degree of certainty that the addition of penicillin and sulfonamides and transfusions to the treatment of children with lymphogenous ]eucemia was associated with an increased time of survival in this series. DISCUSSION
Chronic leucemias are rare in children. 1 Occasional reports of chronic myelogenous leucemia in children have appeared, Steinbrink, 2 Malmberg, 8 Esp, ~ but only a few cases of chronic ]ynlphogenous leucemia in, this age group have ever been authenticated. ~-s The designation of an acute or chronic leucemia is retrospective and dependent in p a r t upon the severity and the duration of the illness. Many cases exhibit a subacute course intermediate between that of acute or chronic leueemia. I n order to avoid a controversy, insoluble at present, the simple designation of lymphogenous leucemia in children was employed. The literature on leucemia in childhood contains several extensive series with data on the incidence, sex distribution, and duration of illness. Cooke, 6 Booth and Rembolt, 1~ Falkenstein and Fowler, ~1 Sullivan, Rice, and Cassidy, 1~ and Dale ~3 summarized data on 282 patients under 14 years of age with ]eucemia, of which 62 per cent were males. The average duration of survival in 252 cases, as measured from the onset of symptoms, was from 3.6 to 5.5 months. The results of Dale ~3 on 38 cases are in almost exact agreement with the presently reported data on children who were not treated, or were treated with transfusions or irradiation. The data combine lymphogenous and myelogenous leucemia (Table I I ) . TABLE I I .
DUI%ATtON OF SURVIVAL IN CHILDREN W I T H LEUCEMIA DURATION
AUTHOR Cooke G B o o t h a n d R e m b o l t 10 Falkensteln and Fowler11 S u l l i v a n e t a112 Dalel3 *Excluding
SOURCE OF . DATE DATES Missouri 1918-1933 Minnesota 1930-1938 Iowa to 1943 Dist. Columbia 1938-1947 1Vew Y o r k 1932-]948
1 c a s e of 34 m o n t h s '
CASES (No.) 50 40 61 63 38 ~
..
AVERAGE (MO~T~S) (MONTHS) SPREAD
0.5-9 0.1-7 0.5-14 0.5-15 0.5-20
.
3.6 4.2 4.3 4.0 5.5
duration.
There is but scanty information in the literature regarding tile influence of supportive treatment on tile course of childhood leucemia and on the length of survival. Most hematologists have seen at least a few instances of transient beneficial effect of blood transfusions on children with acute lymphatic ]eucemia. Schwind 14 observed that infusion of blood plasma was followed by a decrease in the percentage of myeloblasts in the blood. Dreyfus1 ~ has stated that the probability of a remission is related to the number of blood transfusions and the total
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amount of blood infused. Replacement transfusions have also been followed by remissions.16, ~7 On the other hand, Cooke ~ concluded that the effect of transfusions is transient and of questionable value. Palkenstein and F o M e r xl similarly reported that transfusions were given to thirty-four patients, and an analysis of the data revealed no evidence that the administration of blood prolonged the life of the patients. Sullivan and collaborators ~ stated that blood transfusion is the only measure that prolongs life appreciably, but gave no statistical data to support this contention. The present data agree with the conclusions of Cooke G and of Falkenstein and F o M e r ~ in that the group of children who received treatment with irradiation or with blood transfusions alone survived no longer than patients who received no treatment. I t must be realized, however, that the transfusions were given intermittently and not in massive amounts. ~00-
t
~
i 5 0 -
100-
50-
)
5
~
_
O 0 5 "tO DIFFI~I~ENCE B E T W E E N MEAN5 TWO GROUP5 (MONTHS)
OF
Assur~pt ion~ 1, N I = N g . 5 . G r o u p s identical i n a.]l r e s p e c t s therapy.
excepl;
F i g . 4 , - - N u m b e r of e a s e s n e e d e d to d e m o n s t r a t e d i f f e r e n c e s b e t w e e n two t h e r a p e u t i c m e t h o d s in t h e t r e a t m e n t of c h i l d r e n w i t h l y m p h o g e n o u s l e u c e m i a w i t h 50 p e r cent c e r t a i n t y .
In contrast, patients who received treatment with penicillin a n d / o r sulfonamides and with repeated transfusions showed a significant prolongation of life. F r o m these data alone it is of course not possible to determine whether this increase in survival time is the result of some specific actions of the antibiotics and ,blood transfusions against the leucemic manifestations or whether such t h e r a p y exerts its effects merely by improving the genera] condition of the patient and l~y controlling intercurrent infections. , : The employment of penicillin, sulfonamides, and other antibiotic agents have aborted and controlled m a n y infections which f r e q u e n t l y have been the
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461
9t e r m i n a t i n g event in patients with an acute leueemia. In addition, there have been reports of the coagulant p r o p e r t y of the antibiotics, is but they lack confirmation. 19 I f the antibiotics indeed diminish the hemorrhagic tendency in patients with acute ]eueemia, it would indicate a possible favorable effect of these agents in this group of diseases other than of a purely antibacterial nature. One must also consider the chemotherapeutic effect of antibiotic agents on as yet undiscovered infectious agents possibly related etiologically to leucemiaJ Statistical analysis of final results on sufficient numbers of adequately controlled cases is the only method by which prolongation of life or other effects of t h e r a p y can be acceptably, substantiated. This involves comparison of groups of treated patients with similar groups of " u n t r e a t e d controls," or at ]east with groups treated by some other method but similar in regard to sex, age, stage of disease, a n d general condition. The presently reported groups of children with ]eucemia a p p e a r to fu]fill the requirement of coming f r o m the same population. The data also allow statistical estimations of the n u m b e r of cases which would be needed in order to demonstrate differences between the effects of various forms of t r e a t m e n t in childhood leucemia. These calculations are given in Fig. 4. Assuming t h a t the untreated control group of another investigation shows the same mean survival and s t a n d a r d deviation, thirty-seven cases which are treated by a p a r t i c u l a r agent and survive on the average three months longer are necessary, for a conclusion that is statistically significant at the 1 per cent level (P = 0.01), 50 per cent of the time. To be more certain of attaining results significant at the 1 per cent level, a larger n u m b e r of cases would be needed. F o r example, for 95 per cent certainty at the 1 per cent level with a difference of three months between the means of the two groups, the number of cases needed in control and experimental groups rises to 100. The statistical method, therefore, is not only essential in the final evaluation of the data but is as necessary in the formulation of an experimental study in which conclusive results are desired. Evaluation of the t r e a t m e n t of leucemia in children requires an adequate control series of cases. I n clinical therapeutic investigations, it is usual to give supportive t h e r a p y r a t h e r t h a n to withhold t r e a t m e n t of a n y kind. Therefore, the effects of such t h e r a p y must be considered. Heretofore, such supportive t h e r a p y has been considered to have relatively little or no effect on duration of survival. T h a t some folie acid antagonists and other agents produce marked hematological changes in m a n y patients with acute leucemia cannot be denied. 2~ Clinical investigations with these agents hav e proceeded to the point where prolongation of life m a y be used to evaluate their efficacy. The influence of blood transfusions, antibiotics, and antihemorrhagic agents in the clinical management of children with leucemia who also receive such new agents must be considered before the chemical agents alone can be held responsible for the prolongation of life. SUMMARY
1. Ninety cases of lymphogenous leucemia in children under 14 years of age were studied, of which 76 were analyzed relative to duration of survival.
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THE JOURNAL OF PEDIATRICS
2. The average duration of survival of 18 eases of untreated lymphogenous leueemia in children was 5.6 months. 3. A group of 17 children who were treated with irradiation (x-ray or radiophosphorus) plus blood transfusions and antibiotics survived 5.8 months. 4. Twenty-four patients received blood transfusions but no penicillin or sulfonamide t h e r a p y and survived an average of 6.0 months. 5. Seventeen patients who received blood transfusions and antibiotics survived an average of 8.9 months, a significantly prolonged survival time in comparison with the first three groups. 6. The necessity of statistical comparison of patients treated experimentally by chemotherapeutic agents with an adequately controlled comparable group is emphasized. REFERENCES 1. Forkner, C . E . : Leukemia and Allied Disorders, New York, 1988, The Macmillan Co. 2. S t e i n b r i n k , W.: Beitrgge zur Pathologie der B l u t k r a n k h e i t e n , Deutsche reed. Wchnschr. 51: 106-108, 1925. 3. 3/[almberg, hr.: B e i t r a g zur X e n n t n i s der 1Vfyeloiden Leukgmie bei S~nglingen, Aeta Paediat. 4: 410-435, 1925. 4. Esp, E.: Chronische aleukaemische myeloisehe Leuk~mie bei einem 8 jg~hrigen X n a b e , Acta Paediat. 9: 89-117, 1929. 5. Bruin, 3//7. De: Chronlsehe lymphatische Leuki~mie in I(indesalter, Folia t I a e m a t . 48: 433-442, 1932. 6. Cooke, J. V.: Acute Leukemia in Children, J. A. M. A. 101" 432-435, 1933. 7. CoOke, J. V'.. The Incidence of Acute L e u k e m i a in Children, J. A. 3/[. A. 119: 547-550, 1942. 8. Gittins, R.: Studies in the Anemias of I n f a n c y and E a r l y Childhood, V I I I , Leukaemia (leucosis) in Children, Arch. Dis. Childhood 8: 291-322, 1933. 9. Holowach, J.: Chronic Lymphoid Leucemia in Children, J. P~DIAT. 32: 84-86, 1948. 10. Booth, 1VL, and Rembolt, /r R.: Leukemia in Childhood, L a n c e t 59: 216-229, 1939. 11. Falkensteinl D., and Fowler, W . M . : Acute L e u k e m i a in Childhood, Am. J. Dis. Child. 65: 445-454, 1943. 12. Sullivan, R. B., Rice, E. C., and Cassidy, J. E.: Leukemia. A Review of Sixty-Five Cases, Clin. Proc. Child. Hosp., Washington, D. C. 4: 195-207, 1948. 13. Dale, J. If., Jr.: Leucemia in Childhood, J. PEDIAT. 34: 421-432, 1949. 14. Sehwind, J . L . : P a r t i a l lVfaturation of Leukemic Myeloblasts Following F r e s h Plasma Transfusion, Am. J. 1Yr. Sc. 213: 170-175, 1947. 15. Dreyfus, R.: Le r ~ m i s s i o n s d e la leucgmic aigu~, Sang 19: 35-40, 1948. 16. Piney, A.: E x sanguino Transfusion in Acute Leukemia, L a n c e t 2: 379, 1948. 17. Bessis, M.: The Use of Replacement Transfusion in Diseases Other Than ttemolytic Disease of the Newborn, Blood 6: 424-437, 1949. 18. Editorial: A n t i b i o t i c s and Blood Coagulation, J. A. M. A. 141: 924, 1949. 19. Dolkart~ R. E., tIa]pern, B., Larkin, 3/f.~ Day, F. L., and deTakats, G.: The Effect of Penicillin Upon the Clotting A c t i v i t y of Blood in Normal H u m a n Subjects, J. Pharmacol. & Exper. Therap. 96: 291, 1949. 20. F a t h e r , S., Diamond, L. K., Mercer, E. D., Sylvester, R. F., and Wolfe, & A.: Temporary Remissions in Acute Leukemia in Children Produced b y Folio Acid Antagonist, 4-Aminopteroyl Glutamic Acid ( A m i n o p t e r i n ) , New E n g l a n d J. Med. 238: 787-793, 1948. 21. Stickney, J. M., Mills, S. D., tIagedorn, A. B., and Cooper, T.: The T r e a t m e n t of Acute Leukemia W i t h Folic Acid Antagonists, Proc. Staff Meet., Mayo Clinic 24: 525-533, 1949. 22. Weber, E. J., Iiarpinski~ F. E., Jr., and tIeinle, R. W.: The T r e a t m e n t of Acute Leukemias of Childhood W i t h Folic Aeld Antagonists, J. PEI)IAT. 36: 69-78, 1950.