Br. J. Cancer Br. J. Cancer
'."
S92-S95 (1992), XVIII, S92-S95 Suppl. XVIII, 66, Suppl. (1992), 66,
C
Macmillan Press Ltd, 1992 Macmillan
Press
Ltd,
Late effects of early childhood cancer therapy A.T. Meadows, J.A. Gallagher & G.R. Bunin The Children's Hospital of Philadelphia, Division of Oncology, 34th and Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. Summary The late effects of cancer treatment in children diagnosed early in life (under 2 years of age) may be compared to those in children who were over 2 years at the time of diagnosis. Such areas as growth and development (e.g., intellectual and sexual), vital organ function and risk for second cancer are of particular interest. This report reviews late occurring morbidity which was studied in approximately 400 survivors of childhood cancer, 93 of whom were under 2 years of age at diagnosis. The most commonly reported late effect was musculoskeletal in radiation treated patients. More severe cognitive deficits were seen among both age groups cranially irradiated for leukaemia prophylaxis with 24 Gy compared to 18 Gy. Second cancers developed equally between the two age groups. Predisposing factors and/or prior therapy may produce second cancers. There are inherent problems in assessing the outcomes of very young children treated for cancer. Improved survival has only been evident during the last 15 years, a period too short to appreciate many of the end points of interest in adult life. Such patients require a necessarily long follow-up period but this will prove informative in the future as more institutions initiate procedures for extended surveillance.
Concern regarding the long-term effects of cancer chemotherapy and radiotherapy for childhood cancer has prompted studies of survivors for some time. These have recently been reviewed (Walterhouse & Meadows). The question of whether very young children would be more or less susceptible to these effects has also been raised. At least insofar as growth is concerned, we believe that the very young child is at greater risk. On the other hand, there has been some suggestion in the literature that some organs are preferentially protected during early childhood, such as the gonads and perhaps the heart. Nevertheless, there is no longer any doubt regarding the importance of studying the long-term effects of cancer treatment in children. For the reasons cited above an especially strong argument can be made in the case of the child under 2 years of age. However, studies in very young children are considerably more difficult to carry out. There is more uncertainty regarding the effects of treatment and disease in younger children and in predicting their future status. The problems of maintaining contact and follow-up are compounded by the necessarily long interval between probable cure and endpoints of interest in adult life. Such efforts however can be rewarding because of the light they may shed on the mechanisms of organ disruption when developmental processes are deranged. Other reasons for wishing to know these consequences include the need for appropriate counselling for the patient and the family, and the urgent need to modify therapy if outcomes are judged to be so disabling as to seriously compromise the quality of survival. Some years ago we estimated that by the year 2000 one in every 1000 young adults in the third decade of life would be a survivor of childhood cancer. This presumes that 60% of the children with cancer under the age of 15 can be cured. As approximately one in 600 children will be diagnosed with cancer during childhood, and the cure rate predicted has been borne out in those diagnosed during the 1970's, the following equation can be applied to 20-30 year olds: 1/600 x .60 = 1/1000. Questions that arise in the minds of treating physicians and parents include those related to growth and development, particularly intellectual functioning, and sexual maturation. This latter question and those relating to fertility are not easily addressed since not enough older survivors are available for study. The functioning status of vital organs
Correspondence: A.T. Meadows
will remain an open question as aging processes begin to operate. The development of secondary neoplasms, particularly those that are malignant and likely to be resistant to treatment, continue to be of concern. One cannot hope yet to estimate the lifetime excess cancer risk of all children treated for malignant disease, and it is especially difficult to do so for those under the age of two at treatment. Nevertheless, this report attempts to summarise the information available to date regarding the long-term morbidity of very young children. These data come from many sources, including the work done at the Pennsylvania Pediatric Oncology Network (PON) institutions' and the Late Effects Study Group (LESG)2.
Patients and methods Some years ago we were able to evaluate systematically the follow-up status of approximately 400 children with a confirmed malignant diagnosis treated in the PON institutions from 1970 who had survived for at least 5 years beyond their last evidence of disease and who had been off therapy for at least 2 years (Meadows, 1986). This group consisted of 318 children who were over 2 years at diagnosis and 93 who were less than 2 years. Males were in the majority in both groups, comprising 53% of the older children and 56% of the younger ones. The diagnoses differed between the groups with the overwhelming majority of older patients having survived leukaemia (224/318); 47 and 37 had Wilms' tumour and soft tissue sarcoma, respectively (Table I). In the younger group the embryonal tumours predominated with Wilms' tumour, neuroblastoma and retinoblastoma occurring in 24, 22, and 19 patients, respectively. Leukaemia occurred in 19 patients with five of the 19 being less than I year at diagnosis.
There were also differences in the treatment modalities used (Table II). Patients less than 2 years were less likely to have received radiation therapy (RT) than those over 2 years (57% vs 89%). On the other hand, younger patients were 'The Children's Hospital of Philadelphia, The Children's Hospital of Pittsburgh, St Christopher's Hospital for Children, the Geisinger Medical Center and the Hershey Medical Center. 2The Children's Hospital of Philadelphia; Dana-Farber Cancer Institute, Boston, Columbus Children's Hospital; Children's Memorial Hospital, Chicago; Institut Gustave-Roussy, Villejuif; Istituto Nazionale Tumori, Milano; Roswell Park Memorial Institute, Buffalo; Royal Manchester Children's Hospital; Emma Kinderziekenhuis, Amsterdam; University of Minnesota, Minneapolis; Children's Hospital of Los Angeles; Hospital for Sick Children, Toronto.
LATE EFFECTS OF EARLY CHILDHOOD CANCER THERAPY
S93
Table I Diagnoses by age 0-12 months 17 17 13 4 5 56
Wilms' tumour Neuroblastoma Retinoblastoma Soft tissue sarcoma Leukaemia Total
12-24 months
7 5 6 5 14 37
Total 2 years
24 22 19 9 19 93
47 5 5 37 224 318
Table II Treatment modalities by diagnosis and age
Surgery
Chemotherapy
ChemoChemoSurgery and therapy, ChemoSurgery therapy surgery therapy and XRT a and XRT and XRT
Wilms' tumour 12/40 12/7b 5/0 5/0 Neuroblastoma 4/1 8/4 Retinoblastoma 3/0 6/4 3/0 7/1 Soft tissue sarcoma 3/6 0/2 6/29 Leukaemia 6/15 13/209 Total 8/0 6/15 26/17 7/3 13/209 33/74 = aRadiation therapy. bNumber of patients under 2 years at diagnosis (n 93)/number of patients over 2 years at diagnosis (n = 318).
more likely to have been treated with surgery, with or without other modalities. The differences reflect the higher proportion of embryonal tumours in the younger group and the overwhelming prevalence of leukaemia in the older group. The patients were treated between 1970 and 1982. While the younger patients are fairly well distributed over these various eras of diagnosis, the number of older patients evaluated who were treated in the first era is proportionately less (Table III). This is principally because of reduced survival during that period as well as more who were lost to follow-up. The age at follow-up is very different for both groups with many more older patients having had the opportunity to proceed through normal pubertal development, and few such patients in the younger group (Table IV). This results in an underestimate of the long-term toxicities related to sexual maturation. For those patients who did receive RT, the doses were quite different for the younger patients compared with those who were older. This can be seen in a review of the Wilms' tumour patients, since that diagnosis occurred in both groups (Table V). Doses of RT to the flank for the younger and
Table III Era of diagnosis and treatment by age
> 2 years 45 138 135
< 2 years
1970-73 1974-77 1977-82
21 35 37
Table IV Age at follow-up by age at diagnosis 5 -9 years 10-14 years > 14 years
< 2 years
> 2 years
43 38 12
36 93 189
Table V Wilms' tumour: doses of radiation by age No.
Flank Abdominal Lung
10 3 2
< 2 years Med. cGy
1425 1050 1275
> 2 years Med. cGy 34 2400 7 1800 17 1400
older patients were 1425 cGy and 2400 cGy, respectively. Differences for the respective groups were also seen for doses to the abdomen (1050 and 1800) and lungs (1275 and 1400). Overall 40 of 47 older Wilms' tumour patients were treated with RT while only 12 of 24 younger patients were so treated. In general, the drugs received were similar, especially with regard to the proportion having had doxorubicin. Results and discussion
Musculoskeletal abnormalities and growth Musculoskeletal abnormalities were the most common among the late sequelae and all of the affected patients had received radiation therapy (RT) (Table VI). Overall, 33 of 39 irradiated younger patients (85%) with embryonal tumours had some degree of bone or soft tissue abnormality, while 66 of 71 (93%) older children were affected (Table VII). Growth was not specifically evaluated in these patients. However, in another study of growth the effects in children treated with truncal RT, age at RT and dose were the two most significant factors accounting for reduction in stature compared to expected (Silber et al., 1990). There was a greater degree of shortening in younger patients for a given dose of RT to the spine.
Endocrine dysfunction The majority of patients with endocrine dysfunction are girls with ovarian failure. This complication was noted in seven Wilms' tumour patients, five older children with soft tissue sarcomas, and one older girl with neuroblastoma. Of the remaining seven children with soft tissue sarcomas and endocrine failure, four had growth hormone failure and three were hypothyroid. Twenty-one of the older children with leukaemia had some degree of endocrine dysfunction; 11 boys are sterile (following testicular irradiation), three girls have ovarian failure, four have growth hormone failure and three are hypothyroid. Many of the younger children are too young to be evaluated for gonadal function. Our findings must, therefore, be considered very preliminary regarding eventual fertility.
No.
Cardiac dysfunction Other effects which occurred in younger and older patients included cardiac abnormalities (Table VI). All three of the
S94
A.T. MEADOWS et al. Table VI Summary of late effects by group
Wilms' tumour 2 Musculoskeletal ga 35 1 Endocrine 6 3 8 Cardiopulmonary Other organ 2 7 Total # pts 24 47 aNumbers reflect abnormalities rather than
Soft tissue sarcoma 2 26 3 11 1 1 5 0 15 9 37 patients.
Neuroblastoma 2 4 9 1 0 2 1 -
-
22
5
Retinoblastoma 2 1 10
Leukaemia 2 -
-
-
1
25 19
4 5
0 19
14 21
5 224
Table VII Musculoskeletal late effects by age and diagnosis < 2 yrs No. RT Dose %ABNL' 38 12 1425 WTb 33 6 3500 9 STS 41 12 1700 22 NBL 50 4999 9 RB 19 aABNL: abnormal. bWT. Wilms' Tumour; neuroblastoma; RB, retinoblastoma. No. 24
younger Wilms' tumour patients who had some degree of cardiomyopathy had received doxorubicin alone, while the eight patients in the older group so affected had received both doxorubicin and cardiac irradiation. Cardiomyopathy also was seen in survivors of soft tissue sarcoma, neuroblastoma, and one younger patient with leukaemia. The latter, a 14 year old boy was one year of age when he received 650 mg/m2 of daunomycin. His cardiac studies were normal for 8 years and he was asymptomatic for 10 years. One year later he precipitously developed congestive heart failure. We are presently performing an exhaustive cardiac followup study with over 200 children enrolled. Only six were less than 2 years at the time they received treatment and all are well without abnormalities. We aim to be able to detect differences that may exist between younger and older children with respect to abnormalities when similar doses of anthracycline with or without cardiac irradiation are considered. Other organ abnormalities Other organ dysfunction noted in survivors of Wilms' tumour were predominantly genitourinary, occurring in two younger and three older patients. Genitourinary abnormalities were also present in five of the older patients with soft tissue sarcoma, and one retinoblastoma patient under 2 years. The latter child's hematuria was secondary to oral cyclophosphamide therapy. Other consequences of therapy noted in older patients included asplenia, hearing abnormalities and hepatic dysfunction. Enucleations and cataracts were present in both age groups of retinoblastoma, soft tissue sarcoma and leukaemia patients.
Learning disabilities We reported some years ago that children with leukaemia who received 2400 cGy cranial irradiation can develop declines in IQ of approximately 20 points and are delayed in scholastic achievement by approximately 2 years (Meadows et al., 1981; Peckham et al., 1988). However, little is known regarding the outlook for the group of very young children less than 2 years at the time of treatment. We reviewed the records of the 13 younger children with leukaemia in the PON study; eight had been treated with 1800 cGy and five with 2400 cGy. Of the latter five patients two have severe cognitive dysfunction and three are moderately affected. Of those who received 1800 cGy, two have mild learning disabilities, five are apparently unaffected (one of these was treated for relapse at the age of five although she was diag-
> 2 yrs No. RT Dose %ABNL 40 3000 75 25 5600 70 5 3000 80 1 4000 20 STS, soft tissue sarcoma; NBL,
No. 47 37 5 5
nosed at one year of age), and one patient is lost to followup.
Second malignant neoplasms The risk of developing second malignant neoplasms is clearly increased in children surviving cancer (Meadows et al., 1989; Tucker et al., 1983). The factors that predispose to this serious complication include genetic predisposition and therapy, and among the therapeutic agents, radiation, alkylating agents and anthracyclines are implicated. The data presented here with regard to SMN come from the Late Effects Study Group registry where 411 children developed more than one malignant disease; 125 were diagnosed with their first primary when less than 2 years of age. The distribution of primary diagnoses in these two age groups differs markedly (Table VIII). The majority of younger patients had embryonal tumours: retinoblastoma (55), neuroblastoma (24) and Wilms' tumour (15). In the older patients, Hodgkin's disease was the most common primary, occurring in 57 patients, while leukaemia, Wilms' tumour and brain tumours were next in frequency and accounted for 46, 40 and 40 patients, respectively. The proportion of SMN occurring in irradiated fields was similar for the younger and the older patients. Seventy percent of the retinoblastoma patients developed a bone or soft tissue sarcoma as an SMN, a finding consistent with other series (Draper et al., 1986). The retinoblastoma patients comprised three quarters of all bone and soft tissue sarcomas as SMN. In this genetically predisposed group two-thirds developed their sarcomas in the RT field, a fraction similar to the overall radiation-associated frequency. The retinoblastoma gene has been shown to be responsible for predisposing not only to retinoblastoma, but, in some fraction of the genetic cases, to bone and soft tissue sarcomas, as well (Friend et al., 1986). Other primaries in which predisposition was suggested by the absence of carcinogenic treatment included Wilms' tumour in young children, and leukaemia in both young and old patients. In the latter group, the presence of soft tissue sarcomas and leukaemia with breast cancer in young relatives are features consistent with the Li-Fraumeni syndrome (Li, 1969). Neurofibromatosis, the most common genetic disease predisposing to childhood cancer was present in two young children with multiple primary tumours (Schneider et al., 1986). Brain tumours and leukaemia were prominent first neoplasms in the older group, probably a reflection of the increased survival and overall incidence of those neoplasms. In
LATE EFFECTS OF EARLY CHILDHOOD CANCER THERAPY
Primar/a SMN Bone STSA Leukaemia/ lymphoma Brain Thyroid Breast Other Totalc
Table VIII Second malignant neoplasms by age (n = 411) RB HD Wilms' STSA Leukaemia Brain NBL
26/4b 13/1
1/7 5/8
4/13 1/6
4/2 4/4
0/4 0/6
0/3 0/5
0/7 0/4
S95
Bone
1/14 0/7
3/8 1/5 4/1 1/7 0/12 0/23 0/5 2/2 3/5 2/0 1/9 4/12 0/2 0/1 0/6 0/2 5/2 0/3 0/6 0/9 1/3 0/1 0/1 0/0 0/0 0/2 0/4 5/1 7/3 3/6 1/4 4/11 2/8 0/10 55/9 15/40 10/36 24/11 6/40 6/46 0/57 1/31 aRB, retinoblastoma; STSA, soft tissue sarcoma; NBL, neuroblastoma; HD, Hodgkin's disease; Bone Primary (osteogenic sarcoma [0/7] and Ewing's sarcoma [1/24]. bUnder 2 years/Over 2 years at first cancer diagnosis. c125/286: includes eight other first neoplasms in younger patients 17 in older patients.
2/1 7/0
our younger patients, all SMN following a primary diagnosis of leukaemia or brain tumour occurred in association with RT. A Childrens Cancer Study Group analysis of SMN following acute lymphocytic leukaemia revealed a 23-fold excess risk of brain tumours (Neglia, 1991). This complication occurred in 24 children and 23 had received cranial irradiation; all were less than 6 years at the time of treatment. A review of the SMN occurring in the younger patients reveals an absence of breast cancer, in spite of the frequency of chest RT for neuroblastoma, Wilms' tumour and other primaries. Young patients whose chests are irradiated seem to be more susceptible to thyroid neoplasms while those in the second decade at the time of treatment are more likely to develop breast cancer after chest irradiation. However, it may be too early at this time to appreciate an increase in the younger patients' risk of breast cancer following chest RT. Eighteen patients in this registry developed more than two malignant neoplasms; six were less than 2 years of age and this fraction is similar to the overall fraction of registered cases in that younger age group. At least five of the six patients are presumed to have a predisposition to cancer by virtue of having the retinoblastoma gene (two), neurofibromatosis (two), or the Li-Fraumeni syndrome (one). For the patients over 2 years, ten of the 12 were associated with radiation exposure and only four were likely to be related to some known genetic condition.
Summary Young children less than 2 years of age comprise 14% of the childhood cancer population. Concern for the welfare of these very young patients is understandably somewhat greater than the concern for childhood cancer patients generally with respect to the quality of life-long survival. These youngsters are at a much more active phase of growth in all organ systems, and while care has been taken in the past to consider this when treatment options are chosen, there is still generalised uncertainty with regard to the consequences of such modified treatment. The diagnosis in a child less than 2 years of age requires many more years of followup for the documentation of potential long-term disabilities and if our treatment successes began, on average in the middle 1970's, the oldest patients are only now entering the third decade of life. It will be critically important to develop systems for ensuring excellent follow-up of these youngsters so that in 10 or 20 years more information regarding their quality of survival can be appreciated. The authors wish to acknowledge the assistance of the physicians in the Pediatric Oncology Network and the Late Effects Study Group without whose concern and dedication these studies could not have been performed. We are also grateful to Mr J. Elias for his editorial assistance.
References
DRAPER, G.J., SANDERS, B.M. & KINGSTON, J.E. (1986). Second primary neoplasms in patients with retinoblastoma. Br. J. Cancer, 53, 661-671. AN 86243106. FRIEND, S.H., BERNARDS, R., ROGELJ, S., WEINBERG, R.A., RAP-
PAPORT, J.M., ALBERT, D.M, & DRYJA, T.P. (1986). A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature, 323, 643-646. AN 87039336. LI, F.P. & FRAUMENI, J.F. (1969). Soft tissue sarcomas, breast cancer and other neoplasms: A familial syndrome? Ann. Intern. Med., 71, 747-752. AN 70063857. MEADOWS, A.T., GORDON, J., MASSARI, D.J., LITrMAN, P., FERGUSSON, J. & MOSS, K. (1981). Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet, 2, 1015-1018. AN 82079475. MEADOWS, A.T. & HOBBIE, W.L. (1986). The medical consequences of cure. Cancer, 58, 524-528. AN 86244688. MEADOWS, A., OBRINGER, A., MARRERO, O., OBERLIN, O., ROBISON, L., FOSSATI-BELLANI, F., GREEN, D., VOUTE, P.A., MORRIS-JONES, P., GREENBERG, M., BAUM, E & RUYMANN, F.
(1989). Second malignant neoplasms following childhood Hodgkin's disease: Treatment and splenectomy as risk factors Med. Pediatr. Oncol., 17, 477-484. AN 90066123.
NEGLIA, J., MEADOWS, A., ROBISON, L., KIM, T.H., NEWTON, W.A., RUYMANN, F.B., SATHER, H.N. & HAMMOND, G.D. (1991) . Second neoplasms after acute lymphoblastic leukemia in child-
hood. N. Engl. J. Med., 325, 1330-1336.
PECKHAM, V., MEADOWS, A.T., BARTEL, N. & MARRERO, 0.
(1988). Educational late effects in long-term survivors of childhood acute lymphocytic leukemia. Pediatrics, 81, 127-133. AN 88096182.
SCHNEIDER, M., OBRINGER, A.C., ZACKAI, E. & MEADOWS, A.T.
(1986). Childhood neurofibromatosis: Risk factors for malignant disease. Cancer Gen. Cytogen., 21, 347-354. AN 86161420. SILBER, J.H., LITTMAN, P.S. & MEADOWS, A.T. (1990). Stature loss following skeletal irradiation for childhood cancer. J. Clin. Oncol., 8, 1-9. AN 90132838. TUCKER, M.A., MEADOWS, A.T., BOICE, J.D., HOOVER, R.N. &
FRAUMENI, J.F. (1983). Cancer risk following treatment of childhood cancer. In Radiation Carcinogenesis: Epidemiological and Biological Significance, Fraumeni, J.F. & Boice, J.D. (eds), Raven Press: NY pp. 211-224. ISBN: 0890049076. WALTERHOUSE, D.O. & MEADOWS, A.T. (1990). Late effects of childhood Cancer Therapy. In The Complications of Cancer Management, Plowman, P.N., McElwain, T.J., Meadow, A.T. (eds), Butterworth Scientific Ltd: Guildford, Britain, pp. 95-113.
'."
S92-S95 (1992), XVIII, S92-S95 Suppl. XVIII, 66, Suppl. (1992), 66,
C
Macmillan Press Ltd, 1992 Macmillan
Press
Ltd,
Late effects of early childhood cancer therapy A.T. Meadows, J.A. Gallagher & G.R. Bunin The Children's Hospital of Philadelphia, Division of Oncology, 34th and Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. Summary The late effects of cancer treatment in children diagnosed early in life (under 2 years of age) may be compared to those in children who were over 2 years at the time of diagnosis. Such areas as growth and development (e.g., intellectual and sexual), vital organ function and risk for second cancer are of particular interest. This report reviews late occurring morbidity which was studied in approximately 400 survivors of childhood cancer, 93 of whom were under 2 years of age at diagnosis. The most commonly reported late effect was musculoskeletal in radiation treated patients. More severe cognitive deficits were seen among both age groups cranially irradiated for leukaemia prophylaxis with 24 Gy compared to 18 Gy. Second cancers developed equally between the two age groups. Predisposing factors and/or prior therapy may produce second cancers. There are inherent problems in assessing the outcomes of very young children treated for cancer. Improved survival has only been evident during the last 15 years, a period too short to appreciate many of the end points of interest in adult life. Such patients require a necessarily long follow-up period but this will prove informative in the future as more institutions initiate procedures for extended surveillance.
Concern regarding the long-term effects of cancer chemotherapy and radiotherapy for childhood cancer has prompted studies of survivors for some time. These have recently been reviewed (Walterhouse & Meadows). The question of whether very young children would be more or less susceptible to these effects has also been raised. At least insofar as growth is concerned, we believe that the very young child is at greater risk. On the other hand, there has been some suggestion in the literature that some organs are preferentially protected during early childhood, such as the gonads and perhaps the heart. Nevertheless, there is no longer any doubt regarding the importance of studying the long-term effects of cancer treatment in children. For the reasons cited above an especially strong argument can be made in the case of the child under 2 years of age. However, studies in very young children are considerably more difficult to carry out. There is more uncertainty regarding the effects of treatment and disease in younger children and in predicting their future status. The problems of maintaining contact and follow-up are compounded by the necessarily long interval between probable cure and endpoints of interest in adult life. Such efforts however can be rewarding because of the light they may shed on the mechanisms of organ disruption when developmental processes are deranged. Other reasons for wishing to know these consequences include the need for appropriate counselling for the patient and the family, and the urgent need to modify therapy if outcomes are judged to be so disabling as to seriously compromise the quality of survival. Some years ago we estimated that by the year 2000 one in every 1000 young adults in the third decade of life would be a survivor of childhood cancer. This presumes that 60% of the children with cancer under the age of 15 can be cured. As approximately one in 600 children will be diagnosed with cancer during childhood, and the cure rate predicted has been borne out in those diagnosed during the 1970's, the following equation can be applied to 20-30 year olds: 1/600 x .60 = 1/1000. Questions that arise in the minds of treating physicians and parents include those related to growth and development, particularly intellectual functioning, and sexual maturation. This latter question and those relating to fertility are not easily addressed since not enough older survivors are available for study. The functioning status of vital organs
Correspondence: A.T. Meadows
will remain an open question as aging processes begin to operate. The development of secondary neoplasms, particularly those that are malignant and likely to be resistant to treatment, continue to be of concern. One cannot hope yet to estimate the lifetime excess cancer risk of all children treated for malignant disease, and it is especially difficult to do so for those under the age of two at treatment. Nevertheless, this report attempts to summarise the information available to date regarding the long-term morbidity of very young children. These data come from many sources, including the work done at the Pennsylvania Pediatric Oncology Network (PON) institutions' and the Late Effects Study Group (LESG)2.
Patients and methods Some years ago we were able to evaluate systematically the follow-up status of approximately 400 children with a confirmed malignant diagnosis treated in the PON institutions from 1970 who had survived for at least 5 years beyond their last evidence of disease and who had been off therapy for at least 2 years (Meadows, 1986). This group consisted of 318 children who were over 2 years at diagnosis and 93 who were less than 2 years. Males were in the majority in both groups, comprising 53% of the older children and 56% of the younger ones. The diagnoses differed between the groups with the overwhelming majority of older patients having survived leukaemia (224/318); 47 and 37 had Wilms' tumour and soft tissue sarcoma, respectively (Table I). In the younger group the embryonal tumours predominated with Wilms' tumour, neuroblastoma and retinoblastoma occurring in 24, 22, and 19 patients, respectively. Leukaemia occurred in 19 patients with five of the 19 being less than I year at diagnosis.
There were also differences in the treatment modalities used (Table II). Patients less than 2 years were less likely to have received radiation therapy (RT) than those over 2 years (57% vs 89%). On the other hand, younger patients were 'The Children's Hospital of Philadelphia, The Children's Hospital of Pittsburgh, St Christopher's Hospital for Children, the Geisinger Medical Center and the Hershey Medical Center. 2The Children's Hospital of Philadelphia; Dana-Farber Cancer Institute, Boston, Columbus Children's Hospital; Children's Memorial Hospital, Chicago; Institut Gustave-Roussy, Villejuif; Istituto Nazionale Tumori, Milano; Roswell Park Memorial Institute, Buffalo; Royal Manchester Children's Hospital; Emma Kinderziekenhuis, Amsterdam; University of Minnesota, Minneapolis; Children's Hospital of Los Angeles; Hospital for Sick Children, Toronto.
LATE EFFECTS OF EARLY CHILDHOOD CANCER THERAPY
S93
Table I Diagnoses by age 0-12 months 17 17 13 4 5 56
Wilms' tumour Neuroblastoma Retinoblastoma Soft tissue sarcoma Leukaemia Total
12-24 months
7 5 6 5 14 37
Total 2 years
24 22 19 9 19 93
47 5 5 37 224 318
Table II Treatment modalities by diagnosis and age
Surgery
Chemotherapy
ChemoChemoSurgery and therapy, ChemoSurgery therapy surgery therapy and XRT a and XRT and XRT
Wilms' tumour 12/40 12/7b 5/0 5/0 Neuroblastoma 4/1 8/4 Retinoblastoma 3/0 6/4 3/0 7/1 Soft tissue sarcoma 3/6 0/2 6/29 Leukaemia 6/15 13/209 Total 8/0 6/15 26/17 7/3 13/209 33/74 = aRadiation therapy. bNumber of patients under 2 years at diagnosis (n 93)/number of patients over 2 years at diagnosis (n = 318).
more likely to have been treated with surgery, with or without other modalities. The differences reflect the higher proportion of embryonal tumours in the younger group and the overwhelming prevalence of leukaemia in the older group. The patients were treated between 1970 and 1982. While the younger patients are fairly well distributed over these various eras of diagnosis, the number of older patients evaluated who were treated in the first era is proportionately less (Table III). This is principally because of reduced survival during that period as well as more who were lost to follow-up. The age at follow-up is very different for both groups with many more older patients having had the opportunity to proceed through normal pubertal development, and few such patients in the younger group (Table IV). This results in an underestimate of the long-term toxicities related to sexual maturation. For those patients who did receive RT, the doses were quite different for the younger patients compared with those who were older. This can be seen in a review of the Wilms' tumour patients, since that diagnosis occurred in both groups (Table V). Doses of RT to the flank for the younger and
Table III Era of diagnosis and treatment by age
> 2 years 45 138 135
< 2 years
1970-73 1974-77 1977-82
21 35 37
Table IV Age at follow-up by age at diagnosis 5 -9 years 10-14 years > 14 years
< 2 years
> 2 years
43 38 12
36 93 189
Table V Wilms' tumour: doses of radiation by age No.
Flank Abdominal Lung
10 3 2
< 2 years Med. cGy
1425 1050 1275
> 2 years Med. cGy 34 2400 7 1800 17 1400
older patients were 1425 cGy and 2400 cGy, respectively. Differences for the respective groups were also seen for doses to the abdomen (1050 and 1800) and lungs (1275 and 1400). Overall 40 of 47 older Wilms' tumour patients were treated with RT while only 12 of 24 younger patients were so treated. In general, the drugs received were similar, especially with regard to the proportion having had doxorubicin. Results and discussion
Musculoskeletal abnormalities and growth Musculoskeletal abnormalities were the most common among the late sequelae and all of the affected patients had received radiation therapy (RT) (Table VI). Overall, 33 of 39 irradiated younger patients (85%) with embryonal tumours had some degree of bone or soft tissue abnormality, while 66 of 71 (93%) older children were affected (Table VII). Growth was not specifically evaluated in these patients. However, in another study of growth the effects in children treated with truncal RT, age at RT and dose were the two most significant factors accounting for reduction in stature compared to expected (Silber et al., 1990). There was a greater degree of shortening in younger patients for a given dose of RT to the spine.
Endocrine dysfunction The majority of patients with endocrine dysfunction are girls with ovarian failure. This complication was noted in seven Wilms' tumour patients, five older children with soft tissue sarcomas, and one older girl with neuroblastoma. Of the remaining seven children with soft tissue sarcomas and endocrine failure, four had growth hormone failure and three were hypothyroid. Twenty-one of the older children with leukaemia had some degree of endocrine dysfunction; 11 boys are sterile (following testicular irradiation), three girls have ovarian failure, four have growth hormone failure and three are hypothyroid. Many of the younger children are too young to be evaluated for gonadal function. Our findings must, therefore, be considered very preliminary regarding eventual fertility.
No.
Cardiac dysfunction Other effects which occurred in younger and older patients included cardiac abnormalities (Table VI). All three of the
S94
A.T. MEADOWS et al. Table VI Summary of late effects by group
Wilms' tumour 2 Musculoskeletal ga 35 1 Endocrine 6 3 8 Cardiopulmonary Other organ 2 7 Total # pts 24 47 aNumbers reflect abnormalities rather than
Soft tissue sarcoma 2 26 3 11 1 1 5 0 15 9 37 patients.
Neuroblastoma 2 4 9 1 0 2 1 -
-
22
5
Retinoblastoma 2 1 10
Leukaemia 2 -
-
-
1
25 19
4 5
0 19
14 21
5 224
Table VII Musculoskeletal late effects by age and diagnosis < 2 yrs No. RT Dose %ABNL' 38 12 1425 WTb 33 6 3500 9 STS 41 12 1700 22 NBL 50 4999 9 RB 19 aABNL: abnormal. bWT. Wilms' Tumour; neuroblastoma; RB, retinoblastoma. No. 24
younger Wilms' tumour patients who had some degree of cardiomyopathy had received doxorubicin alone, while the eight patients in the older group so affected had received both doxorubicin and cardiac irradiation. Cardiomyopathy also was seen in survivors of soft tissue sarcoma, neuroblastoma, and one younger patient with leukaemia. The latter, a 14 year old boy was one year of age when he received 650 mg/m2 of daunomycin. His cardiac studies were normal for 8 years and he was asymptomatic for 10 years. One year later he precipitously developed congestive heart failure. We are presently performing an exhaustive cardiac followup study with over 200 children enrolled. Only six were less than 2 years at the time they received treatment and all are well without abnormalities. We aim to be able to detect differences that may exist between younger and older children with respect to abnormalities when similar doses of anthracycline with or without cardiac irradiation are considered. Other organ abnormalities Other organ dysfunction noted in survivors of Wilms' tumour were predominantly genitourinary, occurring in two younger and three older patients. Genitourinary abnormalities were also present in five of the older patients with soft tissue sarcoma, and one retinoblastoma patient under 2 years. The latter child's hematuria was secondary to oral cyclophosphamide therapy. Other consequences of therapy noted in older patients included asplenia, hearing abnormalities and hepatic dysfunction. Enucleations and cataracts were present in both age groups of retinoblastoma, soft tissue sarcoma and leukaemia patients.
Learning disabilities We reported some years ago that children with leukaemia who received 2400 cGy cranial irradiation can develop declines in IQ of approximately 20 points and are delayed in scholastic achievement by approximately 2 years (Meadows et al., 1981; Peckham et al., 1988). However, little is known regarding the outlook for the group of very young children less than 2 years at the time of treatment. We reviewed the records of the 13 younger children with leukaemia in the PON study; eight had been treated with 1800 cGy and five with 2400 cGy. Of the latter five patients two have severe cognitive dysfunction and three are moderately affected. Of those who received 1800 cGy, two have mild learning disabilities, five are apparently unaffected (one of these was treated for relapse at the age of five although she was diag-
> 2 yrs No. RT Dose %ABNL 40 3000 75 25 5600 70 5 3000 80 1 4000 20 STS, soft tissue sarcoma; NBL,
No. 47 37 5 5
nosed at one year of age), and one patient is lost to followup.
Second malignant neoplasms The risk of developing second malignant neoplasms is clearly increased in children surviving cancer (Meadows et al., 1989; Tucker et al., 1983). The factors that predispose to this serious complication include genetic predisposition and therapy, and among the therapeutic agents, radiation, alkylating agents and anthracyclines are implicated. The data presented here with regard to SMN come from the Late Effects Study Group registry where 411 children developed more than one malignant disease; 125 were diagnosed with their first primary when less than 2 years of age. The distribution of primary diagnoses in these two age groups differs markedly (Table VIII). The majority of younger patients had embryonal tumours: retinoblastoma (55), neuroblastoma (24) and Wilms' tumour (15). In the older patients, Hodgkin's disease was the most common primary, occurring in 57 patients, while leukaemia, Wilms' tumour and brain tumours were next in frequency and accounted for 46, 40 and 40 patients, respectively. The proportion of SMN occurring in irradiated fields was similar for the younger and the older patients. Seventy percent of the retinoblastoma patients developed a bone or soft tissue sarcoma as an SMN, a finding consistent with other series (Draper et al., 1986). The retinoblastoma patients comprised three quarters of all bone and soft tissue sarcomas as SMN. In this genetically predisposed group two-thirds developed their sarcomas in the RT field, a fraction similar to the overall radiation-associated frequency. The retinoblastoma gene has been shown to be responsible for predisposing not only to retinoblastoma, but, in some fraction of the genetic cases, to bone and soft tissue sarcomas, as well (Friend et al., 1986). Other primaries in which predisposition was suggested by the absence of carcinogenic treatment included Wilms' tumour in young children, and leukaemia in both young and old patients. In the latter group, the presence of soft tissue sarcomas and leukaemia with breast cancer in young relatives are features consistent with the Li-Fraumeni syndrome (Li, 1969). Neurofibromatosis, the most common genetic disease predisposing to childhood cancer was present in two young children with multiple primary tumours (Schneider et al., 1986). Brain tumours and leukaemia were prominent first neoplasms in the older group, probably a reflection of the increased survival and overall incidence of those neoplasms. In
LATE EFFECTS OF EARLY CHILDHOOD CANCER THERAPY
Primar/a SMN Bone STSA Leukaemia/ lymphoma Brain Thyroid Breast Other Totalc
Table VIII Second malignant neoplasms by age (n = 411) RB HD Wilms' STSA Leukaemia Brain NBL
26/4b 13/1
1/7 5/8
4/13 1/6
4/2 4/4
0/4 0/6
0/3 0/5
0/7 0/4
S95
Bone
1/14 0/7
3/8 1/5 4/1 1/7 0/12 0/23 0/5 2/2 3/5 2/0 1/9 4/12 0/2 0/1 0/6 0/2 5/2 0/3 0/6 0/9 1/3 0/1 0/1 0/0 0/0 0/2 0/4 5/1 7/3 3/6 1/4 4/11 2/8 0/10 55/9 15/40 10/36 24/11 6/40 6/46 0/57 1/31 aRB, retinoblastoma; STSA, soft tissue sarcoma; NBL, neuroblastoma; HD, Hodgkin's disease; Bone Primary (osteogenic sarcoma [0/7] and Ewing's sarcoma [1/24]. bUnder 2 years/Over 2 years at first cancer diagnosis. c125/286: includes eight other first neoplasms in younger patients 17 in older patients.
2/1 7/0
our younger patients, all SMN following a primary diagnosis of leukaemia or brain tumour occurred in association with RT. A Childrens Cancer Study Group analysis of SMN following acute lymphocytic leukaemia revealed a 23-fold excess risk of brain tumours (Neglia, 1991). This complication occurred in 24 children and 23 had received cranial irradiation; all were less than 6 years at the time of treatment. A review of the SMN occurring in the younger patients reveals an absence of breast cancer, in spite of the frequency of chest RT for neuroblastoma, Wilms' tumour and other primaries. Young patients whose chests are irradiated seem to be more susceptible to thyroid neoplasms while those in the second decade at the time of treatment are more likely to develop breast cancer after chest irradiation. However, it may be too early at this time to appreciate an increase in the younger patients' risk of breast cancer following chest RT. Eighteen patients in this registry developed more than two malignant neoplasms; six were less than 2 years of age and this fraction is similar to the overall fraction of registered cases in that younger age group. At least five of the six patients are presumed to have a predisposition to cancer by virtue of having the retinoblastoma gene (two), neurofibromatosis (two), or the Li-Fraumeni syndrome (one). For the patients over 2 years, ten of the 12 were associated with radiation exposure and only four were likely to be related to some known genetic condition.
Summary Young children less than 2 years of age comprise 14% of the childhood cancer population. Concern for the welfare of these very young patients is understandably somewhat greater than the concern for childhood cancer patients generally with respect to the quality of life-long survival. These youngsters are at a much more active phase of growth in all organ systems, and while care has been taken in the past to consider this when treatment options are chosen, there is still generalised uncertainty with regard to the consequences of such modified treatment. The diagnosis in a child less than 2 years of age requires many more years of followup for the documentation of potential long-term disabilities and if our treatment successes began, on average in the middle 1970's, the oldest patients are only now entering the third decade of life. It will be critically important to develop systems for ensuring excellent follow-up of these youngsters so that in 10 or 20 years more information regarding their quality of survival can be appreciated. The authors wish to acknowledge the assistance of the physicians in the Pediatric Oncology Network and the Late Effects Study Group without whose concern and dedication these studies could not have been performed. We are also grateful to Mr J. Elias for his editorial assistance.
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