Late Effects of Antileukemic Treatment

The Leukemias

0031-3955/88 $0.00

+ .20

Late Effects of Antileukemic Treatment

Judith Ochs, MD, * and Raymond K. Mulhern, PhDt

By the year 1990, one in every 2000 children reaching the age of 20 will be a survivor of childhood acute lymphoblastic leukemia (ALL).47 As a result, there is a growing concern over the physical and psychological functioning of the survivor population with some studies linking certain undesirable medical sequelae to specific treatment factors. Although different regimens of therapy may yield equivalent cure rates and similar acute toxicities, the frequency, type and severity oflong-term sequelae may differ considerably. 18, 36, 55, 89 Long-term survivors of childhood ALL are defined as those patients who are disease-free at least 5 years from the original diagnosis of ALL and off therapy for at least 2 years. Clinical research has identified three major physical areas of concern: (a) second malignancies; (b) CNS structural changes including ventricular dilatation, calcifications and white-matter hypodensities; and (c) endocrine effects, especially relating to growth and reproductive status. Psychological morbidity can be either neuropsychological or psychosocial. Neuropsychological studies have emphasized elements of CNS functional integrity such as intelligence, memory, attention, and perceptual-motor abilities, while psychosocial studies have focused upon measures of quality of life, such as personal adjustment, social competence, family relationships, and socioeconomic attainment. Unfortunately, there are few prospective longitudinal studies in which physical and psychological changes were measured concurrently, the interrelationship of the changes investigated, and their clinical significance and permanence determined. Developmental aspects of survival after leukemia therapy have been largely ignored. Most studies have been cross-sectional in design and unidimensional in what they measure. Although this discus*Associate Professor of Pediatrics, Department of Pediatrics, University of Tennessee, Memphis College of Medicine, Memphis, Tennessee; Associate Member, Division of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee tAssociate Member and Director, Division of Psychology, St. Jude's Children's Research Hospital, Memphis, Tennessee Supported in part by grants CA-20l80 and CA-21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC).

Pediatric Clinics of North America-Vo!. 35, No.4, August 1988

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sion is subdivided into sections concerning different late effects, long-term sequelae rarely occur in isolation and may be both interrelated and interactive. With the exception of second malignancies, the sequelae to be described are not life-threatening and do occur in other populations of children. Nonetheless, for the child who has already survived a lifethreatening and sometimes painful illness that has marked him or her as different from other children, truly successful treatment must avoid or minimize toxic effects and involve pediatricians, oncologists, family physicians, and other medical specialists in efforts to correct or mitigate undesirable long-term sequelae. During the 1970s, over one-third of children with ALL were cured55 ; today, one half or more are cured. 18, 36, 89 This improvement has come about through the use of therapy that is more aggressive than previous treatment plans, both in the number of drugs and the dosage intensity; cranial irradiation continues to be the most frequently used method of CNS prophylaxis. It is possible that the higher cure rates being obtained with modern therapy will be accompanied by more frequent or more severe sequelae than those described in this article.

SECOND MALIGNANCIES The risk of developing a second malignancy at 20 years following a first malignancy is estimated to be 3 to 12 per cent. 39, 48 Current information shows that 3,46 per 100,000 children per year will be diagnosed as having childhood leukemia and that among these children,49 the risk of developing a second malignancy during or after therapy for ALL is much higher, that is, 62,3 per 100,000 annually. 48, 49 Both genetic and treatment factors have been implicated in the high incidence of second neoplasms after apparently successful treatment for childhood cancers, Well-recognized carcinogens include the alkylating agents, such as cyclophosphamide and ionizing radiation. 27, 29, 72, 86 Immunosuppressive therapy is also associated with an increased frequency of second malignancies. Well-known examples are the lymphomas, which may develop in immunosuppressed renal transplant recipients, 64 Among survivors of childhood ALL, a total of 101 known secondary malignancies have been described (Table 1).1,3,5, 16,41,44-46,48,67, 103 Zarrabi 103 has summarized those reported prior to 1983, at which time hematopoietic malignancies predominated, Since then, the majority of reports have included intracranial neoplasms, The median time to development of a second malignancy involving the hematopoietic or lymphatic system is only 22 months, Thus, the majority of second malignancies seen within 5 years of the original diagnosis of ALL are second leukemias or non-Hodgkin's lymphomas. Whether these represent a second carcinogenic event or a different manifestation of the primary malignant process is unknown. By contrast, secondary solid tumors appear after a median post-diagnosis time of 77 months, with a range of 5 to 15 years, Brain tumors account for almost one-third of secondary solid tumors and, unlike primary brain tumors, are

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Table 1. Second Malignancies in Childhood ALL HE~IATOPOIETIC/LYMPHATIC

TUMORS

(N = 60)

24 14 12 9 1

Acute nonlymphocytic leukemia Hodgkin's lymphoma Chronic myelogenous leukemia Histiocytic medullary reticulosis Non-Hodgkin's lymphoma

SOLID TUMORS (1' = 51)

31 Brain tumors 24 Glioma 3 Ependymoma 3 Lymphoma 1 Meningioma 14 Carcinoma 3 Parotid 3 Basal cell 3 Hepatocellular 2 Thyroid 1 Pancreatic 1 Cervical 1 Breast 6 Other

The median time to diagnosis of second hematopoietic or lymphatic malignancies was 22 months (2 months to 15 years); for solid tumors, it was 6.4 years (1.8-16 years).

predominantly multifocal. 44 Sarcomas and other types of solid tumors are relatively uncommon, The majority of carcinomas and CNS tumors have been reported in patients who received cranial irradiation, Radiation, however, is not a prerequisite to the development of secondary CNS tumors, as three of the reported cases of secondary brain tumors had not received prophylactic irradiation. Interestingly, there are families in which both tumor types have been documented. 22 The type and extent of the second malignancy are important determinants of prognosis: for example, the prognosis for children with secondary brain tumors is poor, whereas certain differentiated carcinomas respond relatively well to treatment. Third malignancies have been reported but only rarely.45 In follow-up studies of a child with ALL, especially if cranial irradiation has been employed for preclinical CNS treatment, careful inspection of the head and neck region should be done, since most secondary carcinomas (thyroid, basal cell, and parotid gland) have occurred in this region. 68 Biopsy should be performed as soon as possible in the event of suspicious skin lesions, nodules or firm, enlarged nodes that do not respond completely to an antibiotic trial. A review of case reports and personal experience has shown that brain tumors in survivors of childhood ALL frequently present with severe headache or sudden onset of severe, obvious neurological deficits. Although meningeal leukemia can cause headaches, symptoms of increased intracranial pressure or focal neurologic defects, meningeal relapses occurring 2 or more years following cessation of therapy are now extremely rare. 25 Thus, if seizures, symptoms of increased intracranial pressure or severe headaches occur in the absence of an obvious clinical explanation, a computed tomography (CT) brain scan or a magnetic resonance image (MRI) scan should be done before lumbar puncture to ensure that an intracranial mass is not present.

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CENTRAL NERVOUS SYSTEM DAMAGE Before the use of effective prophylaxis, the CNS was the most frequent site of first relapse in children with ALL. 22 CNS leukemia was the most likely diagnosis when clinical signs and symptoms of increased intracranial pressure developed; confirmation was readily provided if marked leukemic cell pleocytosis was apparent in cerebrospinal fluid (CSF).11 Treatment of overt CNS leukemia with irradiation or intrathecal injections of methotrexate (IT MTX) or cytarabine was sometimes accompanied by obvious, gradually progressive, therapy-induced encephalopathy clinically evident at a time when leukemic cells were no longer detectable in the CSF.lO Autopsy findings included large areas of calcification and severe white-matter loss with secondary ventricular dilatation in the absence of an inflammatory response. 70 Currently, CNS prophylaxis prevents isolated CNS relapse in over 90 per cent of patients. Five to ten per cent of children experience a CNS relapse, the majority of which occur in asymptomatic patients during maintenance chemotherapy and are detected by routine surveillance lumbar puncture. Close surveillance sometimes makes a conclusive diagnosis of CNS leukemia more difficult since only a small number of leukemic cells may be observed in the CSF. Further morphologic changes mimicking blast transformation may occur secondary to intrathecal therapy. Unfortunately, the treatment of CNS relapse is often accompanied by significant neurotoxicity and neurologic sequelae occur in the majority of patients whose CNS leukemia is eventually cured. The functional and structural CNS changes found in long-term survivors of ALL in continuous remission following effective CNS prophylaxis are less frequent and less severe than in patients who relapse in the CNS, and they have been the focus of intense clinical investigation over the past decade. Certain considerations must be kept in mind when analyzing studies ofCNS changes in long-term survivors of ALL. With few exceptions, the published reports abound in methodologic difficulties such as the lack of consecutive patients, inclusion of patients in continuous complete remission with those who have had a CNS relapse, short follow-up times, crosssectional rather than longitudinal study design, variable methods of CNS prophylaxis and systemic therapy, small sample size, bias of investigators, and variable methods of clinical evaluation and data analysis. Moreover, the large majority of children received cranial irrradiation, and their followup times are considerably longer than those of patients who received intrathecal therapy only. As a result, studies of the latter category of patients are limited, and the intensity and duration of intrathecal therapy received by patients who have been studied to date is generally much less than is used today. Finally, although cranial irradiation is delivered in a relatively uniform manner throughout the world, regimens of intrathecal chemotherapy vary widely with respect to the number of drugs used, the method of dosage calculation, frequency and duration of intrathecal therapy. Neurotoxicity Cranial irradiation followed by weekly intravenous (IV) MTX at doses of 40 mg/m 2 or higher is no longer given because over one-half of children

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Figure 1. CT scans illustrating the difference in the degree of severity of changes following CNS prophylaxis and those than can occur following a meningeal relapse. In the CT scan on the left, a hypodense area of white matter is seen in the frontal horn of a patient who received repeated infusions of intravenous MTX as well as periodic IT MTX. Subtle calcifications (middle CT scan) were seen in another patient after 1800 cGy CrRT and periodic IT MTX. By comparison, the CT scan on the right represents a patient who has had one isolated CNS relapse, significant neurologic dysfunction, and multiple structural changes.

treated in this manner in one study developed severe, irreversible encephalopathy within 1 year/ 7 whether or not there is a postirradiation time interval following which parenteral MTX can be given safely is unknown. The acute and subacute forms of neurotoxicity caused by current methods of CNS prophylaxis, consisting of2400 cGy or 1800 cGy of cranial irradiation and five doses of IT methotrexate, are generally relatively benign and reversible. A possible exception is the 2 to 3 per cent of patients who experience seizures temporally related to intrathecal therapy. 58 Also, 2 to 3 per cent of patients experience L-asparaginase-induced CNS thrombosis. 18, 69 The incidence of long-term neurologic sequelae in patients treated with IT chemotherapy and cranial irradiation is unknown, However, such children clinically appear to recover completely in the acute phase of therapy. Difficulties with fine motor function have been noted as late sequelae, but these complications have been relatively minor. 26 Structural Changes A relatively large number of investigations have described changes such as ventricular dilatation, calcifications and focal areas of white matter hypodensity using cranial CT scans. 2, 12, 14,20,21,26,33,5&--58,65,73 These changes parallel but are considerably less severe than those originally described in autopsy studies of children with CNS leukemia and severe therapy-induced sequelae (see Fig. 1). Comparisons of different series of patients who have not had a CNS relapse and have generally completed therapy, show a wide range in the frequency of changes seen, reflecting varied methods of CNS prophylaxis and systemic therapy, variable criteria used in the classification of changes and variable follow-up times. The few longitudinal studies that have been conducted have disclosed mild ventricular dilatation 73 and hypodensity of white matter that may be reversible, 59 In contrast, the frequency and perhaps severity of calcifications increase with time. 73 Table 2 summarizes many of these studies according to the method of CNS prophylaxis used and illustrates the complexity of the interaction of

Table 2. Frequency of CNS Changes by Type of Prophylaxis* VENTRICULAR CNS PROPHYLAXIS

NO. OF

OR SULCI

CALCIFI-

WHITE MATTER

PATIENTS

DILATATION

CATIONS

HYPODENSITY

Irradiation Plus Intrathecal Chemotherapy 2400 cGy CrRT + 5-8 IT MTX 349 or 2400 cGy CrSpRT

54 (15.5%)

2400 cGy CrRT or IT ara-C 1800 cGy CrRT

+ 35 IT

32

8 (25%)

MTX

48

17 (35%)

1800 cGy CrRT

+ 18

IT MTX

55

+ 5 IT

MTX

No Cranial Irradiation IV MTX (500 mg/m' x 3) + IT MTX IV MTX (1000 mg/m' x 15) + ITMTX IT MTX alone

30 (8.5%)

CO!vIMENTS

12 (3.5%)

6 (18.7%)

4 (12.5%)

0

0

1 (1.9%)

4 (7.2%)

104

4 (3.8%)

52 82

REFERENCE

12, 14, 20, 26,40,56, 57 66,73

3 (5.4%)

Includes changes detected during longitudinal follow-up Aggressive systemic chemotherapy Longitudinal study

59

0

1 «1%)

Ineffective CNS prophylaxis

12, 33, 58

1 (1.9%)

0

10 (19.2%)

Longitudinal study

59

4 (4.6%)

0

3 (3.5%)

Markedly heterogeneous group; majority received ineffective IT chemoprophylaxis

2, 12, 21, 58, 65

26

*Summary of studies in which computed tomography was used to evaluate structural changes in the CNS. Minimal or questionable ventricular dilatation as noted in various studies is not included. The majority of patients in these studies had had their therapy electively discontinued at the time CT scans were performed. Abbreviations: CrRT = cranial radiation therapy, CrSpRT = craniospinal radiation therapy, IT MTX = intrathecal methotrexate, IV MTX = intravenous methotrexate, ara-C = cytarabine.

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CNS and systemic therapy. The largest group of patients received 2400 cGy of cranial irradiation and five concomitant doses of IT MTX. Overall, about 16 per cent had evidence of ventricular dilatation and/or prominent sulci, 9 per cent had calcifications and 4 per cent had areas of white-matter hypodensity. Two series of patients had changes that differed significantly from the overall findings. 14. 40 McIntosh et al. found calcifications in 25 per cent of patients given biweekly parenteral MTX following irradiation. 4o The high frequency of calcifications underscores the as yet poorly understood interaction between irradiation and subsequent parenteral MTX in the pathogenesis of cerebral calcifications. 14 If 2400 cGy cranial irradiation is followed by monthly IT MTX, the frequency of dilatation, calcification, and white matter hypodensity is increased as compared to 2400 cGy cranial irradiation plus five doses of IT therapy.66. 73 The comparison of changes following 2400 cGy cranial irradiation plus five doses of IT therapy versus 1800 cGy plus 18 doses IT therapy59 shows an increased frequency of ventricular dilatation with the latter approach. However, comparisons of the frequency of CNS changes among patients who had received 1800 cGy cranial irrradiation and five concomitant doses of IT therapy26 versus those who received 1800 cGy cranial irradiation and prolonged IT therapy59 disclosed fewer alterations with more IT MTX. This seeming paradox probably reflects the use of much more aggressive systemic therapy in the patients who received only five doses of IT therapy. Finally, comparison of irradiated versus nonirradiated patients has shown that with three courses of moderate-dose MTX and six doses of IT MTX, CT scan changes rarely occur; however, this method of CNS prophylaxis has proved relatively ineffective. With more frequent use of IV and IT MTX, 20 per cent of the patients have white-matter changes, which are reversible in one-half of patients. Calcifications, originally attributed to MTX, have not yet been reported in patients who did not receive irradiation. Other than therapy, a factor that may influence the frequency and type of CT findings is a younger age, 14, 73 although one group has reported more changes in older age children. 26 Only one group of investigators has reported a positive correlation between structural and functional CNS changes. Their analysis indicates a positive relationship between ventricular dilatation and verbal fluency defects in one study,13 and hypothalamicpituitary dysfunction in another,62 with calcifications associated with increased memory loss.13 Consequently, the actual clinical significance of CT scan changes remains unknown, and children with such changes should not be labeled as having "encephalopathy"-a clinical diagnosis for subjects with severe and usually irreversible neurologic dysfunction. More sensitive imaging techniques such as MRI scanning are likely to increase both the frequency and magnitude of structural CNS abnormalities seen and hopefully will lead to firmer conclusions about the etiology and pathogenesis of observed lesions. 63 Central Nervous System Relapse Some children who are cured after an isolated CNS relapse have significant, permanent neurologic sequelae. In one retrospective review of the entire clinical course and outcome of 28 long-term survivors who were

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cured after having had one or two CNS relapses, one-half had had seizures (often status epilepticus) while receiving intrathecal therapy, two had had residual severe hearing loss and one was hemiplegic. One-half of those who had cranial CT scans done had moderate-to-severe calcifications, whitematter loss and/or ventricular dilatation evident on CT scan (see Fig. Ie). The average full-scale IQ was significantly lower than the average full-scale IQ in contemporaries who had not had a CNS relapse. 60 If a second course of irradiation is required, the total dosage of CNS irradiation approximates that given to children with brain tumors. In addition to neurologic sequelae, there is a significant risk of hypothalamicpituitary dysfunction with growth retardation, possible hypopituitarism, and, rarely, radionecrosis. 67 In these children, efforts must be directed to maintaining academic skills, with early referral to a psychologist and provision for remedial courses. After a child is off therapy for 1 to 2 years following an isolated CNS relapse, periodic evaluation of the hypothalamic-pituitary axis is necessary; a significant change in neurologic status should prompt immediate investigation. Neuropsychological Outcome Soni and co-workers in 1975 failed to find neuropsychological deficits in children being treated for ALL.88 Since then, more than 40 studies have been published on this topic, but many questions remain unanswered and serious controversies persist. The majority of studies comparing long-term survivors with normative populations or siblings have demonstrated at least some intellectual deficits and have implicated irradiation in the genesis of these changes. Beyond that level, conclusions are difficult to make with any reasonable degree of certainty, since findings of specific deficits have seldom been replicated. Both Williams and Davis lOO and Fletcher and Copeland 24 have provided scholarly contemporary reviews, in which they identified several common methodologic problems in addition to those previously noted. A lack of appropriate comparison or control groups, selection biases, small sample sizes limiting statistical power and reliability, and contamination of study groups by inclusion of previously relapsed patients are particularly troublesome. In addition, prospective studies in this area have not been as successful as one would like, because the average age at diagnosis has been 4 years. Baseline evaluations of intellect, which are useful for later comparisons, are simply not available. Published neuropsychological studies with positive findings greatly outnumber those showing no deficits, but the former have more critical methodologic flaws. We have, therefore, restricted our discussion to several recent representative investigations that are more technically rigorous, with a preference for those in which patients were consecutively enrolled and/ or randomly assigned to treatment groups. The two risk factors most often implicated in the development of neuropsychological deficits are prophylactic treatment of the CNS with cranial irradiation, with or without intrathecal therapy, and the child's age at the time of CNS treatment. Younger children, especially those under 5 years of age who are treated with 2400 cGy of cranial irradiation, are

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Table 3. Neuropsychological Studies of Long-Term Survivors of ALL l<;O.OF

DELETERIOUS EFFECTS

STUDY GROUP

PATIEl<;TS

YOUNGER AGE

CrRT

REFERENCE

+ CrRT (1800 cGy)

20

No

No

53

IT + IV MTX IT MTX + CrRT (2400 cGy)

20 28

NE

Yes

19

25 8

No

No

98

10 43

Yes

NE

30

IT MTX versus

versus

IT MTX versus Solid tumor controls IT MTX + CrRT (2400 cGy)

24

versus

IT MTX IT MTX

+ CrRT (age <3 yr)

versus

IT MTX + CrRT (age 3-6 yr) versus IT MTX + CrRT (age >7 yr) versus Sibling controls (no treatment)

43 43 67

Abbreviations: IT MTX = intrathecal methotrexate, CrRT = cranial radiation therapy, IV MTX = intravenous methotrexate, NE = Not evaluated.

believed to suffer the greatest damage. Table 3 summarizes several studies that consider these risk factors. 19,30.52.98 Memory is most commonly implicated in studies of late effects as having significant or potentially significant deterioration. In a recent assessment of long-term survivors of ALL, 40 children in a cohort of 56 with ALL in continuous complete remission were given a battery of tests to assess memory functioning 5 years after CNS prophylaxis. 53 All children were free of CNS disease at diagnosis and had been randomly assigned to receive CNS prophylaxis with either 1800 cGy cranial irradiation plus IT MTX or IT MTX plus high-dose IV MTX. No treatment- or age-related differences were seen on 16 standardized memory measures or IQ tests. However, scores of the combined sample were significantly lower than agecorrected norms on a test of visual-spatial memory and on four scales of verbal memory. The mild long-term neuropsychological sequelae in these survivors of ALL appeared to stem from some common factor, such as the disease itself or systemic and intrathecal chemotherapy. Copeland et al. compared the neuropsychological performance of 24 long-term survivors of ALL who had received CNS prophylaxis consisting of intrathecal therapy alone with 25 who had received intrathecal therapy and 2400 cGy cranial irradiation and with a heterogeneous group of 24 long-term survivors of solid tumors who had not received any CNS treatment. 19 The group of children with ALL who were treated with IT MTX and cranial irradiation scored significantly lower than the other two groups on IQ measures, arithmetic achievement, and other neuropsychological functions, although their mean performance generally remained in the normal range. The detrimental role of cranial irradiation in determining

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neuropsychological deficits in long-term survivors was again suggested, but no age-related effects were reported. An exhaustive neuropsychological assessment of children surviving ALL was conducted by Whitt et al. 98 Consecutively admitted patients had been randomly assigned to two CNS prophylaxis groups with or without irradiation. No differences were found between the two groups, although both groups performed somewhat lower than the norm on measures of intellect and achievement. Again, these findings imply that intrathecal therapy and factors other than cranial irradiation affected the neuropsychological performance of survivors. A well-controlled study from the Hospital for Sick Children suggests that a younger age at treatment is a major risk factor for the development of neuropsychological deficits.30 Children with ALL given CNS prophylaxis with IT MTX and cranial irradiation at less than 3 years of age, 3 to 6 years of age, and over 7 years of age were compared with sibling controls. Although patients were generally functioning within the normal range, the greatest disparity between patient and sibling performance was observed among children treated at less than 3 years of age, and these deficits increased with time from therapy. The neuropsychological consequences of treatment in children with CNS relapse appear more severe than in children who remain in remission. We recently conducted a retrospective review of 40 patients 2 to 13 years after CNS relapse. The mean full-scale IQ was 87.5, with academic achievement also in the low-average range for age. Children who were treated for CNS relapse also scored significantly lower than a comparison group of children with ALL who had remained in remission. A second course of cranial irradiation, a young age at relapse, and abnormal CT findings were predictive of lower neuropsychological performance. Brouwers and colleagues are among the few who have attempted to correlate neuropsychological deficits in long-term survivors with neurodiagnostic evidence derived by CT examinations. 13 Ten children with normal CT findings, five with calcifications, and eight with cortical atrophy were compared by means of neuropsychological evaluation. Children with abnormal CT findings, especially those with calcifications, performed more poorly. Memory functions were more severely affected than other measures.

ENDOCRINE EFFECTS Endocrine abnormalities involving the hypothalamic-pituitary axis are probably secondary to cranial irradiation while gonadal dysfunction is probably secondary to chemotherapy. Younger age may increase the risk for subsequent growth problems and decrease the risk for gonadal dysfunction. Growth One-quarter to one-half of children with ALL have reduced secretion of growth hormone in response to different provocative stimuli. 4, 7, 32, 62, 81, 82, 84, 95 The incidence and severity of this deficit are a function of both total

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radiation dose and dose per fraction; younger patients who receive higher total or fractionated irradiation doses are at greatest risk for growth retardation. 81, 82 Because these biochemical abnormalities did not correlate with a significant decrease in yearly growth velocity after the end of therapy, the findings were thought to be of little clinical significance. 6, 84. 90 Notably, however, final height was seldom attained in the patients studied. Recently, investigators from the Children's Cancer Study Group reported a significant decrease in final height attained when they compared height at diagnosis with a median of 7.2 years later in 140 survivors of childhood ALL.74 We have recently done a detailed retrospective review of the growth of 74 boys and 83 girls diagnosed before 1976 and still in continuous remission who had received either 2400 cGy cranial or craniospinal irradiation as CNS prophylaxis. 80 Thirty-five per cent of the boys and 48 per cent of the girls had lost equivalent to 1.5 or more standard deviations in height, with the net result being the almost one-third of the boys' final heights were less than 5 feet 4 inches and those of the girls, less than 5 feet 1 inches. A decrease in eventual height was seen both in patients who had received 2400 cGy of either cranial or craniospinal irradiation. Growth deceleration occurred during treatment and was followed by a period of normal growth velocity after cessation of therapy. A second period of growth deceleration coincided with early adolescence. It is unknown whatever the loss of height is due to a shortened pubertal growth phase or an overall decrease in the magnitude of growth throughout the pubertal years. A recent study of 10 girls treated for ALL noted a subnormal peak height velocity during the second year before menarche and speculated that a relative growth hormone deficiency in combination with early onset of puberty could account for this loss in final height. 50 Studies are needed to assess the correlations between various treatment factors, age at diagnosis, biochemical abnormalities, pubertal development, and final height attained. The benefits of growth hormone therapy are unknown, with conflicting results from different investigators. 76, 101 Thyroid Approximately 3 to 7 per cent of the total dose of prophylactic cranial irradiation is absorbed by the thyroid gland. In a cross-sectional evaluation of 175 long-term survivors of childhood ALL, 158 (90.4 per cent) were found to be euthyroid, 5 (3.0 per cent) to have primary hypothyroidism, 11 (6 per cent) to have compensated hypothyroidism and only 1 (0.6 per cent) to have transient hyperthyroxinemia. Two of the euthyroid patients had secondary thyroid malignancies, and 8 of the 11 patients with compensated hypothyroidism eventually became euthyroid. Females and those with a cranial irradiation dose per fraction of 150 cGy or higher were found to have such abnormalities more often. 75 Gonadal Function Infertility is the most frequently expressed concern of long-term survivors of childhood ALL and their families. Unfortunately, this potential problem area is perhaps the least well-studied. Specific information on gonadal function due to various therapies in cancer survivors is largely

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unavailable. As the median age at diagnosis is 4 years, the majority of children are prepubertal and remain so for a prolonged period afterwards. In the prepubertal child, biochemical measurements such as folliclestimulating hormone levels are not helpful in assessing current or future gonadal function. 83 Thus, the frequency of recovery of gonadal function in damaged children is undefined. The degree of correlation of histopathologic changes with eventual reproductive capability also remains unknown. 94 Finally, the development of secondary sex characteristics does not necessarily mean that germinal cells are present or functional. 79 Boys. In a study of 44 boys, Lendon found that mean tubular fertility index (percentage of seminiferous tubules containing identifiable spermatogonia) was (a) less than that of normal controls, suggesting that the leukemic process itself may modify testicular morphology; (b) significantly affected by previous therapy with more than 1 gm cyclophosphamide or cytosine arabinoside; and (c) improved with passage of time off therapy. The degree of morphologic damage to the testes was not significantly different between prepubertal, early pubertal or late pubertal groups. Luteinizing hormone-releasing hormone and human chorionic gonadotropin stimulation tests indicated elevated follicle-stimulating hormone levels in 1 of 32 prepubertal boys and 5 of 12 older boys.38 In one prospective study of 14 boys with ALL, 2 months to 8.5 years off therapy, all progressed normally through gonadal maturation and developed secondary sex characteristics. Results of semen analysis were normal in the six patients tested. 8 Patients who experience a testicular relapse receive 2400 cGy of bilateral testicular irradiation as part of their therapy. Sterility is the usual result; in addition, this subset of patients is at risk for Leydig cell dysfunction. 9 In these patients, one must evaluate growth as well as perform biochemical studies to determine if testosterone supplementation is necessary. Growth hormone therapy may be necessary in addition to the male hormonal therapy, and care must be taken to ensure maximal growth as well as the development of secondary sex characteristics. In adolescence, testicular implants will probably be necessary for cosmetic reasons. Girls. In contrast to studies of male survivors of childhood ALL, information on the eventual reproductive capacity of girls and its relationship to specific drugs or therapy is extremely limited. It is thought that ova are more resistant to harmful effects of chemotherapy than are spermatogonia. Siris examined pubertal development and reproductive function in 35 girls and women with ALL or non-Hodgkin's lymphoma. 87 Twenty-eight (80 per cent) had normal pubertal progression; seven patients were abnormal, with low levels of serum gonadotropin detected in four and primary ovarian dysfunction in three. Pubertal status was important, as one of 17 prepubertal girls experienced altered pubertal progression compared with 6 of 18 who had leukemia and chemotherapy during puberty or after menarche. A recent report of ovarian dysfunction in young women receiving etoposide (VP-16) as a single agent is of concern as the podophyllotoxins are being increasingly used. 102

BONE MARROW TRANSPLANT Finally, a small group of children who relapse can ultimately be cured of their disease with use of an allogeneic (or syngeneic) bone marrow

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transplant. Preparative regimens commonly include high-dose cyclophosphamide plus total-body irradiation. In addition, glucocorticoid or methotrexate treatment is frequently given for chronic graft-versus-host disease. In a recent report of 142 children who survived more than 1 year after transplantation, 39 per cent were found to have abnormal thyroid-stimulating hormone and/or T4 levels and 24 per cent subnormal adrenocortical function; 17 of 25 patients who had had pretransplant cranial irradiation showed growth hormone deficiency. Height velocity was decreased in all patients and, after transplantation, height was negatively affected by chronic graft-versus-host disease and single-dose total-body irradiation. Sixty-eight per cent of the patients had delayed development of secondary sex characteristics, and gonadal failure occurred in nearly all patients who were postpubertal at transplant. 77 Chronic graft-versus-host disease may develop in up to one-third of the children and is a pleiotropic syndrome with variable severity, time of onset and organ systems involved. In those children with severe graftversus-host disease, major courses of morbidity are scleroderma with contractures and ulcerations, dry eyes and mouth, pulmonary insufficiency and wasting. 85 Cataracts are also a frequent complication and must be monitored for in the first 5 years following bone marrow transplant. Finally, it is likely that significant adverse CNS sequelae will be described in this group. 92

PSYCHOSOCIAL OUTCOME Few studies have addressed the psychosocial status of long-term survivors of ALL. More commonly, psychosocial studies have focused on frequently occurring acute and subacute problems, such as chemotherapyinduced nausea and vomiting, coping with painful medical procedures, and school and family adjustment. 34 Even studies that specifically assess the psychosocial status of long-term survivors of childhood cancer are often hampered by small sample sizes, which makes meaningful statements about a single diagnostic group, such as childhood ALL, extremely difficult. Koocher and O'Malley studied 117 patients who were free of cancer, had been diagnosed as children 5 years or more earlier and were off treatment 1 year or more. 35 Interviews, psychometric testing, and selfreport data were analyzed. Combined adjustment ratings revealed that 53 per cent of the patients were well adjusted, 26 per cent showed mild adjustment problems, 10 per cent moderate problems, and 11 per cent marked to severe problems. Compared with a matched group of 22 patients with chronic but non-neoplastic disease, the cancer survivors showed a higher incidence of psychopathology and lower levels of life satisfaction. Among children treated for ALL, 63 per cent exhibited some adjustment problems, second only to survivors of Hodgkin's disease (64 per cent). A low socioeconomic status, an older age at diagnosis, tumor recurrence, longer duration of treatment, a longer interval between diagnosis and awareness that the diagnosis was cancer, and a shorter time since diagnosis were associated with more adjustment problems.

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Fifty-one brothers and fifty sisters of long-term survivors participating in the Koocher and O'Malley study were also interviewed. The siblings were not, however, analyzed according to the patient's type of cancer. Feelings of jealousy among siblings while the patients were receiving treatment were common and persisted to the date of follow-up analysis. Jealousy and guilt appeared to be exacerbated by inadequate information about the disease and its treatment and by problems in family communication. The authors also noted chronic anxieties related to health fears in 13 per cent of the sibling sample. Psychosocial problems among 450 long-term survivors of childhood cancer drawn from the Connecticut Tumor Registry and 587 healthy siblings have also been reported. 91 No differences in the frequency of major depressive syndromes, suicide attempts, or hospitalizations for psychiatric reasons were noted among patients, siblings, and the general population. Patients had a greater frequency of rejection for military service and for life and health insurance than did their siblings. The number of patients (12) treated for ALL was under-represented in the sample, preventing separate analysis of this group. In one well-designed study, the psychological adjustment of 42 children treated for ALL was compared with their siblings, 42 matched controls, and the siblings of the controls using the Child Behavior Checklist, a standardized parental report.78 Patients reported more behavioral problems in patients than in the three comparison groups. Additionally, decreased social skill attainment and worse school performance were noted in patients treated for ALL. Siblings of controls exhibited adjustment that was not significantly different from that of the controls or siblings of patients. We assessed the behavioral adjustment and social competence of 183 survivors of childhood cancer who were 10 years of age or younger at the time of diagnosis. All children were disease-free, had been off therapy 2 or more years, and were 5 or more years from diagnosis. The incidence of clinically significant problems was as follows: lowered participation in activities, 18 per cent; inadequate social relations, 25 per cent; poor school performance, 33 per cent; somatic complaints of undetermined etiology, 33 per cent; and behavioral problems, 24 per cent, compared with a 7 per cent incidence in the general population. Specifically, children treated for ALL had a greater risk for school-related problems, including grades repeated and special educational placement, than their solid tumor counterparts. 54 Psychosocial stress may continue long after therapy for ALL has been completed. One source of continuing anxiety is the uncertainty about relapse, with the attendant renewal of therapy and a poorer prognosis for survival. Financial burdens placed upon the family during the child's treatment may also persist. Even with insurance, it has been estimated that the direct cost of treatment represents an average of 25 per cent of the family's weekly income, and that significant indebtedness may continue after a child completes therapy. 37 CONCLUSION Once the diagnosis of childhood ALL is made, patients are usually referred to a specialized cancer treatment center, where an oncologist

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assumes primary responsibility. Such centers also offer the services of social workers and psychologists as well as other key members of a multidisciplinary health-care team. As time off therapy increases, long-term sequelae may begin to emerge; coincidentally, visits to the oncologist or referral center decrease in frequency. Unfortunately, for both the patient and the primary care physician, there are as yet no firm guidelines as to the best ways or means of monitoring cured patients for delayed physical or psychological sequelae. Clinical judgments related to the management of these patients are sometimes complicated by uncertainty as to whether a particular problem existed prior to the diagnosis of ALL, whether the problem is secondary to therapy or to the life-threatening illness, or whether all three scenarios are involved. This article has considered only the undesirable sequelae of cancer therapy. In this sense, it resembles a newspaper article, omitting the thousands of long-term survivors of ALL who function quite well on a dayto-day basis and therefore do not "make the news." ACKNOWLEDGMENTS We thank Drs. Larry Kun and William Crist for their thoughtful reviews, Ms. Sharon Ann Morris for medical editing, and Ms. Peggy Vandiveer for typing the manuscript.

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