Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131.

PURPOSE: The high-risk stratum of Children's Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone. PATIENTS AND METHODS: Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy. RESULTS: Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% v 90.6% ± 2.3% (P = .85), and 96.3% ± 1.5% v 96.7% ± 1.4% (P = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT. CONCLUSION: Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.

Case control study of periconceptional folic acid intake and nervous system tumors in children.

PURPOSE: Since 1992, the Centers for Disease Control and Prevention recommends that women of childbearing age consume 400 µg of folic acid per day to reduce the risk of neural tube defects (NTD). It has been speculated that both NTD and nervous system tumors (NST) may share common mechanisms of altered development. It examines the association between folic acid supplementation and the risk for childhood NST. METHODS: Incident cases of children with cancer in Spain registered between 2004 and 2006 were identified through the MACAPE Network Group. Tumors were classified as tumors derived from the neuroectoderm (cases) and those with a mesoderm origin (controls). In a second analysis, NST were further divided into central nervous system tumors (CNST) and sympathetic nervous system tumors (SNST). We compared folic acid supplementation between the groups. RESULTS: Overall, folic acid supplementation any time during pregnancy was similar between cases and controls (odds ratio (OR)=1.05; 95% confidence interval (CI) 0.92-1.20). However, supplementation before the 21st and 36th days of gestation resulted in significantly lower NST than in children with mesoderm tumors (OR=0.34; 95% CI 0.17-0.69 and OR=0.58; 95% CI 0.37-0.91, respectively). Preconceptional intakes of folic acid were also lower in NST although marginally nonsignificant (OR=0.44; 95% CI 0.10-1.02). When NST were divided into CNST and SNST, significant differences between tumors of mesoderm origin were only found for CNST. CONCLUSIONS: Our results support the hypothesis that folate supplementation reduces the risk of childhood NST, especially CNST. The specific mechanism and cellular role that folate may play in the development of CNST have yet to be elucidated.

Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium.

The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.

[Neuroblastoma in children: clinical and biological aspects. An experience of screening in France]. / Le neuroblastome de l'enfant: aspects cliniques et biologiques. Une expérience de dépistage en France.

Neuroblastoma is the commonest solid tumour in children under the age of 5 years (50% of cases before 2 years, 90% before 5) and the second cause of death after accidents. Approximately one child in 10,000 develops neuroblastoma by the age of 15 years. The situation in other European and North American countries is similar to that in France. As neuroblastoma is derived from the sympathetic nervous tissues, it is associated with the production of large amounts of catecholamines and their metabolites which are excreted in the urine. Less than 5% of cases do not produce catecholamines. Vanillylmandelic acid (VMA), homovanillic acid (HVA) and dopamine (DA) are the most useful chemical markers for the diagnosis and clinical control of neuroblastoma. They are generally measured using the reliable and sensitive high pressure liquid chromatography (HPLC). Survival is related to stage (the Evan's staging protocol has been superseded by the INNS staging), and age at diagnosis. There is almost 100% survival for stages I and IIa before the age of 12 months, and less than 20% for stage IV when diagnosed after 2 years of age. Multiple copies of the N-myc oncogene, deletions of chromosome 1p, and diploidy in tumour cells are associated with poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[The inhibiting effect of ortofen and indomethacin in relation to the development of induced nervous system tumors in rats]. / Tormoziashchii éffekt ortofena i indometatsina v otnoshenii razvitiia indutsirovannykh opukholei nervnoi sistemy u krys.

The anticarcinogenic effects of the nonsteroidal antiinflammatory drugs ortophen and indomethacin on carcinogenesis of the nervous and renal systems were studied. Glial tumors of the brain and spinal cord, neurinomas of peripheral nerves and renal mesenchymal tumors were induced in rats through a single transplacental administration of N-ethyl-N-nitrosourea, 75 mg/kg body weight. Ortophen and indomethacin each used in a dose of 20 mg/litre of drinking water in the period of postnatal life were effective in inhibiting the growth of brain and spinal cord tumors, showed a statistically insignificant tendency to suppress the growth of peripheral nervous tumors, but failed to affect the growth of renal tumors.

Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

[The inhibiting effect of epsilon-aminocaproic acid on the incidence of induced tumors of the esophagus, nervous system and kidneys]. / Tormoziashchee vliianie épsilon-aminokapronovoi kisloty na chastotu indutsirovannykh opukholei pishchevoda, nervnoi sistemy i pochek.

The anticarcinogenic properties of epsilon-aminocaproic acid were studied in two rat models of carcinogenesis. Esophageal tumors were induced by oral instillations of a total dose of 54 mg/kg body weight N-methyl-N-benzylnitrosamine whereas tumors of the nervous system and kidney-by transplacental injection of 75 mg/kg body weight N-ethyl-N-nitrosourea. epsilon-Aminocaproic acid given at a concentration of 1 milligram drinking water at the post-initiation stage of the carcinogenesis was shown to inhibit the induction of cancer and papilloma of the esophagus, brain glioma, peripheral nerve neurinoma and mesenchymal tumors of the kidney.

[The anticarcinogenic effects of fumaric acid on models of carcinogenesis in the esophagus, nervous system and kidney]. / Izuchenie antikantserogennykh éffektov fumarovoi kisloty na modeliakh kantserogeneza v pishchevode, nervnoi sisteme i pochke.

Anticarcinogenic effects of the fumaric acid was studied in two rat models of carcinogenesis. Tumors of the esophagus, forestomach, tongue and throat were induced by peroral instillation of 35 mg/kg body weight N-methyl-N-benzylnitrosamine, and neurogenic and renal ones--by transplacental injection of 75 mg/kg body weight N-ethyl-N-nitrosourea. The fumaric acid given in drinking water in the dose of 1 g/l at the postinitiation stage of the carcinogenesis was shown to inhibit the development of esophageal papilloma, brain glioma and mesenchymal tumors of the kidney.

[The inhibiting effect of phytoadaptogenic preparations from bioginseng, Eleutherococcus senticosus and Rhaponticum carthamoides on the development of nervous system tumors in rats induced by N-nitrosoethylurea]. / Tormoziashchii éffekt fitoadaptogennykh preparatov biozhen'shenia, éleuterokokka koliuchego i levzei saflovidnoi na razvitie opukholei nervnoi sistemy u krys, indutsirovannykh N-nitrozoétilmochevinoi.

The study was concerned with the inhibitory effect of officinal preparations of phytoadaptogenic drugs such as bioginseng and Eleutherococcus senticosus and Rhaponticum carthamoides root extracts on the carcinogenesis induced by transplacental administration of N-nitrosoethylurea. The phytodrugs were given orally over a year. The administration of the drugs was followed by longer survival of the rats and lower occurrence and/or multiplicity of tumors (mainly those of the central nervous system). The drugs were placed in the order of decreasing anticarcinogenic activity as follows: bioginseng, Rhaponticum carthamoides extract and Eleutherococcus senticosus extract.

Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study.

This paper reports a study of the Cancer and Leukemia Group B (CALGB) comparing daunorubicin (DNR) or mitoxantrone (DHAD) in induction followed by multidrug intensification over 8 months in adult patients with acute lymphocytic leukemia (ALL). A total of 164 newly diagnosed patients were randomly assigned to either DNR or DHAD plus vincristine, prednisone and methotrexate given intravenously (i.v.) and interthecally (i.t.). Patients received four more intensification courses of chemotherapy and then all therapy was stopped. Central nervous system (CNS) prophylaxis consisted of nine infusions of intermediate dose methotrexate (MTX) and intrathecal MTX. DHAD and DNR were equally effective in producing complete remissions (63 and 65%, respectively). The estimated median remission duration is 10.2 and 12.3 months for the DHAD and DNR arms, respectively (p = 0.56). This study was stopped earlier than planned when it became apparent that remission duration for both arms was shorter than seen in our prior study in which all patients received more than 1 year of maintenance therapy. The estimated median survival is 18.3 and 20.6 months for the DHAD and DNR arms, respectively (p = 0.90). Younger patients and patients with a pre-treatment white blood count of less than 30,000/microliters had a significantly longer remission duration and survival. Eleven per cent of patients who achieved a complete remission have had a CNS relapse to date, which is not different from the rate in our prior study using cranial irradiation and i.t. MTX, implying that intermediate dose MTX with i.t. MTX may be as effective as cranial irradiation and i.t. MTX. This study suggests that some form of maintenance chemotherapy is required for the eradication of residual leukemia cells.

Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension.

A series of 15 consecutive children with head and neck nonorbital rhabdomyosarcoma (RMSA) with meningeal extension were prospectively treated with chemotherapy consisting of Adriamycin (doxorubicin; Adria Laboratory, Columbus, OH) (ADM), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) followed by radiotherapy (60 Gy) to the primary tumor volume, along with intrathecal methotrexate (IT MTX). Thirteen of 15 responded to preradiation chemotherapy. Four of 13 relapsed. Relapse occurred at the level of the primary tumor in three of four. The 3-year progression-free survival (PFS) was 59%, similar to that achieved in a previous series treated with a comparable therapeutic approach that also included whole-brain radiotherapy as a prophylaxis of possible occult meningeal seeding. It is concluded that CNS prophylaxis with radiotherapy is questionable in the management of childhood RMSA with meningeal extension.

Radiotherapy vs intrathecal chemotherapy for CNS prophylaxis in childhood ALL.

Prophylaxis of the central nervous system against meningeal leukemia is a complex problem. There is no optimal solution that is universal for all patients. Instead, treatment must be individualized for the patient's age, prognostic group, and the concomitant systemic chemotherapy. Radiation, because of its CNS toxicity and potential carcinogenicity, is reserved for those in the highest risk groups. For these patients, 1,800 cGy cranial radiation plus intrathecal methotrexate during induction, consolidation, and maintenance therapy is recommended. For other patients, protection should be limited to systemic and intrathecal chemotherapy. Further studies are needed to compare the most effective intrathecal methotrexate prophylaxis with triple intrathecal drug therapy.

Comparison of intermittent or continuous methotrexate plus 6-mercaptopurine in regimens for standard-risk acute lymphoblastic leukemia in childhood (JCCLSG-S811). The Japanese Children's Cancer and Leukemia Study Group.

From 1981 to 1983, 131 previously untreated patients with acute lymphoblastic leukemia (ALL) standard-risk group were entered to the protocol JCCLSG-S811. Of 119 eligible patients, 115 (96.6%) attained complete remission by treatment with prednisone (PRD) plus vincristine (VCR) or vindesine (VDS). After preventive central nervous system (CNS) therapy including 18 Gy cranial irradiation and three doses of intrathecal methotrexate (MTX), the patients were assigned randomly to the two maintenance chemotherapies, Regimen A and Regimen B. Regimen A (intermittent regimen) consisted of PRD (120 mg/m2/day by mouth for 5 days) plus 6-mercaptopurine (6MP) (175 mg/m2/day by mouth for 5 days) plus VCR (2.0 mg/m2 intravenously) alternating biweekly with MTX (225 mg/m2 intravenously). Regimen B (continuous regimen) consisted of 6MP (50 mg/m2/day by mouth) plus MTX (20 mg/m2/week by mouth) combined with pulses of PRD and VCR (the same dosages as Regimen A) every 4 weeks. As the late intensification therapy (LIT), five courses of high-dose MTX (2000 mg/m2 per dose per week intravenously for three doses every 12 weeks) with leucovorin rescue were administered to all patients who were in continuous complete remission (CCR) for more than 2 years. Sixty and 55 patients, respectively, were registered in Regimen A and B. The CCR rates in Regimen A and B were 75.1% +/- 5.8% (mean +/- 1 SE) and 49.7% +/- 7.3% (P less than 0.01) at 4 years, and 72.1% +/- 6.3% and 49.7% +/- 7.3% (P less than 0.05) at 5 years, respectively. In Regimen B, CNS and testicular relapses increased after 3 years of CCR. In addition, the patients in Regimen B had a much higher incidence of infections than Regimen A. The LIT did not seem to have important effects on the duration of CCR. From these data we conclude that the intermittent cyclic regimen of 6MP and MTX may be more effective as compared to the continuous administration of these drugs in the maintenance chemotherapy.

Memory function in disease-free survivors of childhood acute lymphocytic leukemia given CNS prophylaxis with or without 1,800 cGy cranial irradiation.

Previous studies have found that CNS prophylaxis of children with leukemia, especially young children receiving cranial irradiation, causes neuropsychologic deficits. In the present study, 40 children in continuous complete remission from acute lymphocytic leukemia (ALL) were given a battery of tests to assess memory functioning 5 years after CNS prophylaxis. All children were free of CNS disease at diagnosis and had been randomly assigned to receive CNS prophylaxis with either 1,800 cGy cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or IT MTX plus intravenous (IV) high-dose MTX (HDMTX). No treatment- or age-related differences were seen on 16 standardized memory measures. However, scores of the combined sample were significantly lower than age-corrected norms on a test of visual-spatial memory and on four scales of verbal memory. Differences in methods or intensity of CNS prophylaxis and study group selection criteria are proposed to explain our findings and to resolve discrepancies with previous reports. The long-term neuropsychological sequelae in these survivors of ALL may be attributable to some common factor, such as the disease itself or systemic and IT chemotherapy.

Teniposide and cytarabine combination chemotherapy in the treatment of relapsed adolescent and adult acute lymphoblastic leukemia.

Nineteen adolescents and adults with relapsed acute lymphoblastic leukemia (ALL) were treated with teniposide (VM-26) plus cytarabine (ara-C). Eight patients (42%) achieved complete remission. Infection and bleeding secondary to myelosuppression were the most serious complications seen. Responders received periodic reinductions with VM-26 and ara-C, but all relapsed within 16 weeks from remission. Our data demonstrate the effectiveness of combination chemotherapy with VM-26 plus ara-C in adolescent and adult ALL in relapse and suggest testing of this combination in first-line protocols. For remission maintenance, the association of other drug combinations is necessary.

Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse.

Six hundred thirty-four children with acute lymphoblastic leukemia (ALL) were randomized to receive sanctuary therapy consisting of either cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or three courses of intermediate-dose methotrexate (IDM) plus intrathecal methotrexate. Two hundred sixty-six male patients achieved a complete response and were evaluable for the effects of prophylactic therapy on the duration of remission. There was one isolated testicular relapse (0.8%) in the IDM group compared with 14 (10%) in the CRT group. The incidence of testicular relapse was significantly lower in the patients treated with IDM (P less than 0.001). High plasma levels of MTX achieved during the 24-hour infusions may result in increased penetration of MTX into the interstitium of the testes, thus allowing for the eradication of sequestered leukemic cells and preventing the emergence of drug resistance resulting from exposure to sublethal concentration of MTX.