CT scans of long-term survivors of various childhood malignancies

Forty-two children with various systemic malignancies in continuous remission for 1 to 3 years after the completion of chemotherapy had CT scans with normal ventricular dimensions, similar to a noncancer “control” population. Seventeen of these patients had acute lymphocytic leukemia (ALL) treated either with prophylactic cranial irradiation and intrathecal methotrexate [7] or intrathecal methotrexate alone [10] and the remaining 25 patients had soft tissue sarcomas. Sixteen other patients with sarcomatous meningitis had enlarged ventricles while on chemotherapy. Nine had ALL. Seven had soft tissue sarcomas, none of whom received any prior CNS irradiation or intrathecal chemotherapy. In this retrospective study no evidence of hydrocephalus or significant white matter hypodensity was detected in long-term survivors of childhood cancer, regardless of whether prophylactic intrathecal chemotherapy and/or cranial irradiation was given. Direct involvement of the CNS with meningeal cancer was the most important association with ventriculomegaly.     

Treatment of meningeal relapse in childhood acute lymphoblastic leukemia: II. A prospective study of intellectual loss specific to CNS relapse and therapy

Changes in intellectual function during the course of treatment for acute lymphocytic leukemia were studied. Twenty-four children had baseline psychological evaluations and annual reevaluations for 3-6 years postdiagnosis. Treatment in all patients included combination chemotherapy, 2,400 cGy prophylactic cranial irradiation, and intrathecal methotrexate. Central Nervous System (CNS) relapse occurred in eight of these children. It was then treated with 3,000 cGy cranial plus 1,800 cGy spinal irradiation. Patients who remained in continuous complete remission showed no decline in global intelligence quotient (IQ). Patients who experienced CNS relapse had a mean decline of 16 IQ points by 3 years postdiagnosis and the long-term survivors displayed a mean loss of 25 IQ points 5-6 years postdiagnosis. Three of the five long-term survivors of CNS relapse function within the retarded range of mental ability and require special education. The other two have learning problems and display poor academic performance relative to same-age peers. There was no association noted between age at diagnosis and ultimate loss of IQ points. This prospective study suggests that children who receive a second course of cranial irradiation for treatment of CNS relapse are at high risk for significant and progressive intellectual loss.     

Isolated cerebral calcifications after prophylactic treatment of cerebromeningeal involvement of acute lymphoblastic leukemia: relation of psycho-intellectual sequelae

Intracranial calcifications were demonstrated by CT scan in 5 children after complete remission of acute lymphoblastic leukemia (ALL). Initial treatment included prophylactic irradiation of central nervous system and intrathecal methotrexate. Behavioral abnormalities or learning difficulties were clinically apparent in all children at the time of the radiologic examination. Isolated intracranial calcifications represent one of possible cerebral sequelae that are to be found in 53% of children receiving treatment for ALL. No fine correlation between direct toxic effect of methotrexate or, post-radiation lesion, and neuro-psychological sequelae can be done. In an attempt to avoid some of this sequelae, suppression of cranial irradiation from ALL treatment protocols is now studied.     

Long-term control of central nervous system leukaemia.

Seventy-four children with acute lymphoblastic leukaemia had one or more episodes of central nervous system (CNS) leukaemia. 5 children had CNS involvement at diagnosis; 4 survived for less than one year. In 35 children who had not had a previous bone marrow relapse on treatment and who received combination chemotherapy, the median duration of haematological remission from the time of first CNS relapse was almost 3 years. 5 children received full dose (2400 rads) craniospinal irradiation after their first CNS relapse; 4 have remained in CNS and haematological remission for 2 1/2 years or more. 18 children who had a CNS relapse after irradiation received 4-weekly intrathecal methotrexate; in 8 children this was given via an intraventricular reservoir. The median duration of CNS remission in children receiving intrathecal methotrexate was 2 years. Systemic and intrathecal treatment was stopped in 7 children after 2 1/2 years in continuous remission and in 2 children after 2 years. 4 of these 9 children remain in remission at intervals from 41 to 69 weeks off treatment but one is severely retarded. These results show that CNS disease is compatible with prolonged survival, but illustrate the difficulties of eradicating established CNS leukaemia.     

COMPUTED TOMOGRAPHIC FINDINGS OF THE BRAIN IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA AFTER CENTRAL NERVOUS SYSTEM PROPHYLAXIS WITHOUT CRANIAL IRRADIATION

Abstract. Nineteen children in primary remission of acute lymphocytic leukemia (ALL) were investigated by computed tomographic (CT) scans of the brain 2 to 64 (mean 19) months after the central nervous system (CNS) prophylaxis was finished. The CNS prophylaxis consisted of high dose Methotrexate (HDM) intravenously combined with 6–8 doses of Methotrexate intrathecally. Two children received only Methotrexate intrathecally as CNS prophylaxis. In addition three children with ALL who had CNS leukemia were investigated by CT scans of the brain. Only one abnormal CT scan was found among the nineteen asymptomatic children, and one of the three patients with CNS relapse had slightly dilatated subarachnoidal spaces. These results compared with other reports in literature in which the CNS prophylaxis has consisted of intrathecal Methotrexate and cranial irradiation, suggest that there are fewer abnormal CT findings of the brain in patients not receiving cranial irradiation as part of CNS prophylaxis.     

Computed tomographic findings of the brain in children with acute lymphocytic leukemia after central nervous system prophylaxis without cranial irradiation.

Nineteen children in primary remission of acute lymphocytic leukemia (ALL) were investigated by computed tomographic (CT) scans of the brain 2 to 64 (mean 19) months after the central nervous system (CNS) prophylaxis was finished. The CNS prophylaxis consisted of high dose Methotrexate (HDM) intravenously combined with 6--8 doses of Methotrexate intrathecally. Two children received only Methotrexate intrathecally as CNS prophylaxis. In addition three children with ALL who had CNS leukemia were investigated by CT scans of the brain. Only one abnormal CT scan was found among the nineteen asymptomatic children, and one of the three patients with CNS relapse had slightly dilatated subarachnoidal spaces. These results compared with other reports in literature in which the CNS prophylaxis has consisted of intrathecal Methotrexate and cranial irradiation, suggest that there are fewer abnormal CT findings of the brain in patients not receiving cranial irradiation as part of CNS prophylaxis.     

High-dose methotrexate in childhood all

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m². The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m². The highest dose, 33.6 g/m², has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m²     

HIGH-DOSE METHOTREXATE IN CHILDHOOD ALL

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m². The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m². The highest dose, 33.6 g/m², has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m²     

PROGNOSTIC VALUE OF DAY 14 BLAST PERCENTAGE AND THE ABSOLUTE BLAST INDEX IN BONE MARROW OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).     

Methotrexate infusions as central nervous system prophylaxis in children with acute lymphocytic leukemia: the Norwegian experience

This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).     

Remission maintenance of adult acute lymphoblastic leukemia

This report describes the results of a study of central nervous system (CNS) prophylaxis and combination chemotherapy for the maintenance of remission in adult acute lymphoblastic leukemia. Adults with acute lymphoblastic leukemia who achieved complete remission were treated with 2,400 rads cranial irradiation and intrathecal methotrexate for CNS prophylaxis followed by continuation systemic chemotherapy with oral methotrexate, 6-mercaptopurine and cyclophosphamide. There were no CNS relapses following treatment. One-half of the patients relapsed within 11 months, with 5 patients remaining in remission for 27+ to 31+ months. The toxicity was acceptable with no treatment-related deaths. This regimen is capable of producing long remissions in a significant proportion of adults with acute lymphoblastic leukemia and appears to be effective in reducing the incidence of CNS relapse. It has the additional advantage of ease of administration and can be largely administered in the community.     

Remission maintenance of adult acute lymphoblastic leukemia.

This report describes the results of a study of central nervous system (CNS) prophylaxis and combination chemotherapy for the maintenance of remission in adult acute lymphoblastic leukemia. Adults with acute lymphoblastic leukemia who achieved complete remission were treated with 2,400 rads cranial irradiation and intrathecal methotrexate for CNS prophylaxis followed by continuation systemic chemotherapy with oral methotrexate, 6-mercaptopurine and cyclophosphamide. There were no CNS relapses following treatment. One-half of the patients relapsed within 11 months, with 5 patients remaining in remission for 27+ to 31+ months. The toxicity was acceptable with no treatment-related deaths. This regimen is capable of producing long remissions in a significant proportion of adults with acute lymphoblastic leukemia and appears to be effective in reducing the incidence of CNS relapse. It has the additional advantage of ease of administration and can be largely administered in the community.     

小儿急性淋巴细胞白血病中枢神经系统白血病诊治现状

中枢神经系统白血病(CNSL)的防治是小儿急性淋巴细胞白血病(ALL)治疗的一部分。诊断时高白细胞计数、T细胞型及分子遗传学为t(4;11)和Ph 是CNS复发的危险因素,脑脊液不同检查结果的预后价值有待明确。头颅放疗已不用于标危ALL患儿,头颅放疗的预防剂量已减为12Gy,鞘内及全身化疗对CNSL的治疗有重要作用。部分小儿CNS复发经挽救治疗可以长期存活,早期CNS复发的患儿应在第2次CR期进行异基因骨髓移植。     

Effects of radiotherapy on the growth of children with leukemia

The five-year over all survival rates of childhood lymphoblastic leukemia (ALL) have recently increased to more than 80%. During recent years, CNS radiation doses delivered to all children with ALL according to international guideline protocols have decreased. In the 1980s, the prophylactic radiation dose to the CNS decreased from 2400 cGy to 1800 cGy; in the 1990s chemotherapy alone with intrathecal chemotherapy demonstrated that there was no need for prophylactic CNS radiation in standard risk ALL, except in CNS relapse and high risk patients. Late effects on pituitary function and growth were reported by most endocrinologists involved in the follow-up of the cancer survivors. The long-term effects of cranial irradiation on growth in children treated for ALL are reviewed, specifically addressing the deficit in final height, contributing factors for height deficits, growth catch-up after stopping therapy, and growth hormone replacement therapy.     

Prolonged intrathecal chemotherapy replacing cranial irradiation in high-risk acute lymphatic leukaemia: Long-term follow up with cerebral computed tomography scans and endocrinological studies

Cranial irradiation in children with acute lymphatic leukaemia (ALL) decreases the risk of CNS relapse but is associated with serious long-term side-effects. We present the long-term outcome of 21 children with high-risk ALL who received prolonged intrathecal chemotherapy instead of the recommended cranial irradiation. Intrathecal triple therapy (methotrexate, hydrocortisone, and cytarabine) was administered every 2nd month throughout the maintenance phase. The average number of courses of intrathecal methotrexate was 8.7 and of triple 9.0. The 5-year event-free survival was 79%. No CNS relapses occurred. CT scan was performed at diagnosis, at cessation of therapy, and 3 years thereafter. No density abnormalities, pathological contrast enhancement, ventricular dilatation, or calcifications were found. One child showed cortical atrophy both at diagnosis and at cessation of therapy. There was a slight decrease in height SDS with time but no change in weight SDS. Delayed bone age was found in 5 children. No abnormalities of growth hormone, thyroid, adrenal, or gonadal function were observed.Conclusion The study indicates that extended intrathecal chemotherapy in children with high-risk ALL may provide an effective protection from CNS relapses and is associated with a low risk of long-term side-effects.     

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.     

Long-term survivors of acute lymphoblastic leukemia — risk of relapse after cessation of therapy

The results of cessation of therapy (COT) in 64 long-term survivors (disease-free survival of five years or more) of acute lymphoblastic leukemia (ALL) were analyzed to determine the incidence of relapse off therapy. Thirty-seven of the patients had intermittent central nervous system (CNS) prophylaxis. Total follow-up from diagnosis varied from 5.75 to 27.75 years. The median time off therapy was three years (range, 8 months to 26 years). Eighty-six percent (55/64) of the patients continue in their initial remission. Eight patients had relapse, and one patient had a morphologically different leukemia at recurrence. All the relapses occurred between five to eight years from diagnosis and the cumulative rate of relapse for this period was 0.14. There was no significant difference in the rate of relapse for those receiving CNS prophylaxis (0.08) versus those not receiving CNS prophylaxis (0.19). The difference in the relapse rates for boys (0.24) versus girls (0.04) was statistically significant (P=0.04). Isolated testicular relapse (ITR) was not seen in any of the 34 boys. The present study confirms the earlier observations by others that relapse is uncommon in ALL patients remaining in remission longer than seven to eight years. ALL patients treated with intermittent CNS prophylaxis administered throughout the period of maintenance chemotherapy appear to be at no greater risk for relapse off therapy than those treated with high-dose initial cranial irradiation and intrathecal methotrexate. The longer duration of therapy and the use of a repetitive reinduction regimen for maintainance seem to be associated with a decreased risk of ITR after discontinuation of therapy for boys and men. There appears to be a small but definite risk of “second” leukemia in the long-term survivors of leukemia.     

Neurotoxicity due to central nervous system therapy for childhood leukemia

Therapy for occult or overt meningeal leukemia produces subclinical or clinical neurotoxicity in a variable proportion of children with acute lymphoblastic leukemia (ALL). The type, frequency, and permanence of these central nervous system (CNS) changes depend primarily on the therapy itself, although the contribution of additional factors, such as young age, may be substantial. Neurotoxicity in patients who have received 2,400 cGy cranial irradiation plus 5 concurrent doses of intrathecal methotrexate as CNS prophylaxis has been characterized more fully than the CNS changes accompanying other forms of therapy. Cross-sectional studies using cranial computed tomography scans to evaluate structural changes in the brain have shown ventricular dilatation in 15%, white matter hypodensity in 3.5%, and calcifications in 8%. The principal neuroendocrine effect is decreased growth velocity during therapy and adolescence, with significant decreases in final height in approximately one-third of children. Secondary cerebral gliomas with a poor prognosis are being reported with increasing regularity, but the true risk of this complication is still unknown. Use of parenteral methotrexate as the sole method of CNS prophylaxis is associated with transient focal white matter hypodensity. Neuroendocrine and neuropsychologic sequelae associated with this therapy are minimal; however, much of the available information is based on patients treated with regimens that had unacceptably high CNS relapse rates or whose length of follow-up was brief. With more aggressive, and hence more effective, prophylaxis with intrathecal methotrexate, spinal cord myelopathy may become a significant new area of neurotoxicity. Clinically significant CNS toxicity develops in the majority of patients who receive treatment for meningeal relapse. The leukemia itself is a prime contributing factor to this neurotoxicity. In patients who are subsequently cured of leukemia, acute neurotoxicity consists mainly of seizures; the most significant sequelae appearing after the cessation of therapy consists of significant drops in full scale IQ.     

The results of high risk children's acute lyrnphoblastic leukemia total therapy. A report from the Polish children's leukemia/lymphoma study group

The study evaluates the efficacy of seven drug systemic therapy and three drug intrathecal treatment in children with acute lymphoblastic leukemia (ALL). Three hundred and thirty-five children with ALL treated at six hematological centers in Poland were divided into two groups: standard group and high risk group according to the BFM score method. Ninety-two children estimated as high risk patients diagnosed between 1978 and 1981 were treated according to the Polish Children's Leukemia/Lymphoma Study Group (PCLSG) program adopted from LSA₂L₂ regimen. The patients received prednisone, vincristine, adriamycin and cyclophosphamide as remission induction treatment, followed by cytarabin and 6-thioguanine given as consolidation therapy. The central nervous system prophylaxis consisted of cranial irradiation and intrathecal methotrexate, cytarabin and hydrocortisone. In maintenance phase, three different drug combinations were given as intermittent therapy. The total duration of therapy was 2.5 years. The life table analysis showed a 38% disease free survival and 50% complete continuous remission (CCR) for the total group of patients. A relatively high incidence of CNS relapse was observed. These results indicated that the regimen applied was not satisfactorily effective for the increased risk of ALL. Three of seven evaluated prognostic indices—age, mediastinal mass and cytochemical features—were significantly associated with probability of survival of the patients with protocol applied. Some other therapy proposals are discussed.     

Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia

In 1971, Cancer and Leukemia Group B (CALGB) mounted a study of acute lymphocytic leukemia (ALL) that compared the effects of the two steroid hormones dexa-methasome and prednisone. Six-hundred-forty-six children and adolescents with ALL were randomized to receive either prednisone or dexamethasone as part of their remission induction therapy. The 493 evaluable patients who achieved complete remission received the same steroid as pulses throughout remission. Specific central nervous system (CNS) therapy was randomized to either six injections of intrathecal methotrexate (IT MTX) alone or to six injections of IT MTX with cranial radiation (2,400 cGy). Both cranial radiation and dexamethasone offered increased protection against CNS relapse as the first site of failure over IT MTX alone. There were 30 CNS relapses among 238 patients (12.6%) receiving cranial radiation plus IT MTX, whereas there were 70 CNS relapses among 225 (P < 0.001) (22.5%) in those who received IT MTX alone. Similarly, there were 33 CNS relapses among 231 (14.3%) children treated with dexamethasone, whereas there were 67 CNS relapses among 262 (25.6%) treated with prednisone (P = 0.017). Both steroids appeared equal in protecting the bone marrow. Recent national studies have shown significant improvements in preventing CNS relapse over the results in the present report. However, this finding warrants further investigation and, with further documentation, could lead to the substitution of prednisone by dexamethasone to aid further in preventing CNS relapse. This may be particularly important in patients at higher risk for CNS relapse.