Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report.

OBJECTIVE: Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. METHODS: The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. RESULTS: In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. CONCLUSION: GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.

Protección funcional ovárica con análogos de GnRH y preservación de la fertilidad en adolescentes durante la terapéutica oncológica / Protection of the ovarian function with GnRH analogs and preservation of fertility during cancer therapy

Objetivos: Investigar si los análogos de GnRH pueden evitar la falla ovárica precoz post-quimioterapia antineoplásica y tener así un efecto protector de la fertilidad. Diseño del Estudio: Veintiún pacientes oncológicas fueron divididas en dos grupos y seguidas a lo largo de 18 años. A: premenarca, 3-7,5 años (n:5) recibió poliquimioterapia (PCT). B: post-menarca, 14,7 - 20 años (N:12), ciclos menstruales ovulatorios normales, recibieron análogos de GnRH antes de la PCT.B1 (n:5) trasplante de médula ósea previo (BMT) a la PCY.B2 (n:7) recibió PCT y cobaltoterapia supradiafragmática. C: post-menarca, 15,9 - 20 años (n:4) recibió PCT y fue sometida a BMT. La inhibición se obtuvo mediante la administración de acetato de Leuprolide de depósito en dosis mensuales antes y durante la poliquimioterapia. Resultados: A: menarca espontánea (12.17.8 años), ciclos menstruales ovulatorios normales, cinco embarazos normales. B: ciclos ovulatorios normales desde la supresión del análogo de GnRH, tres embarazos. C: amenorrea hipergonadotrófica hipoestrogénica. Conclusiones: El seguimiento de estas pacientes demostró que la administración de análogos de GnRH antes y durante la poliquimioterapia protege la función ovárica y preserva la fertilidad futura de las adolescentes

Protección funcional ovárica con análogos de GnRH y preservación de la fertilidad en adolescentes durante la terapéutica oncológica / Protection of the ovarian function with GnRH analogs and preservation of fertility during cancer therapy

Objetivos: Investigar si los análogos de GnRH pueden evitar la falla ovárica precoz post-quimioterapia antineoplásica y tener así un efecto protector de la fertilidad. Diseño del Estudio: Veintiún pacientes oncológicas fueron divididas en dos grupos y seguidas a lo largo de 18 años. A: premenarca, 3-7,5 años (n:5) recibió poliquimioterapia (PCT). B: post-menarca, 14,7 - 20 años (N:12), ciclos menstruales ovulatorios normales, recibieron análogos de GnRH antes de la PCT.B1 (n:5) trasplante de médula ósea previo (BMT) a la PCY.B2 (n:7) recibió PCT y cobaltoterapia supradiafragmática. C: post-menarca, 15,9 - 20 años (n:4) recibió PCT y fue sometida a BMT. La inhibición se obtuvo mediante la administración de acetato de Leuprolide de depósito en dosis mensuales antes y durante la poliquimioterapia. Resultados: A: menarca espontánea (12.17.8 años), ciclos menstruales ovulatorios normales, cinco embarazos normales. B: ciclos ovulatorios normales desde la supresión del análogo de GnRH, tres embarazos. C: amenorrea hipergonadotrófica hipoestrogénica. Conclusiones: El seguimiento de estas pacientes demostró que la administración de análogos de GnRH antes y durante la poliquimioterapia protege la función ovárica y preserva la fertilidad futura de las adolescentes (AU)

Results of treatment with an intensive combination induction regimen containing idarubicin in children with acute myeloblastic leukemia: preliminary report of the Argentine Group for Treatment of Acute Leukemia.

In April 1990, the Argentine Group for Treatment of Acute Leukemia began a multicenter trial for the treatment of previously untreated acute myeloblastic leukemia patients who were under 21 years of age. Initial treatment consisted of an 8-day induction phase with cytarabine together with idarubicin on days 3 to 5 and etoposide on days 6 to 8. A multidrug consolidation phase was subsequently administered and, after a treatment-free interval of 2 to 4 weeks, two 5-day intensification courses with high-dose cytarabine and etoposide were delivered with a 4-week interval between each course. Continuation therapy was started 2 to 4 weeks after the second course, with 6-thioguanine daily and cytarabine daily for 4 days every 4 weeks. Treatment was stopped after 18 months in children in continuous complete remission. A preliminary evaluation of this ongoing study included 36 patients with a mean age of 7.5 years (age range, 5 months to 16 years). The majority of patients had a French-American-British classification of M2 (n = 13) or M4 (n = 8). Complete remission was achieved by 91.7% of patients, while one died from sepsis in bone marrow hypoplasia and two were regarded as treatment failures. At a median follow-up of 12 months (range, 2 to 23 months) there were 12 adverse events: six bone marrow relapses, one bone marrow/skin relapse, and five deaths in complete remission (all deaths occurred during the consolidation phase). During the induction phase most of the patients experienced prolonged myelosuppression, and grade 3 to 4 toxicity (according to the Children's Cancer Group criteria) was frequently seen. Alopecia was universal. However, toxicity was manageable. We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with acute myeloblastic leukemia.

[Advances in the treatment of acute myeloid leukemia in children. Experience of the Argentinian Group of Acute Leukemia Treatment and the Latin American Group of Malignant Hemopathies Treatment 1967-1987]. / Progresos en el tratamiento de la leucemia mieloide aguda en niños. Experiencia del GATLA/GLATHEM 1967-1987.

Three hundred and seventy-one children below 16 years, with newly diagnosed acute myeloid leukaemia, were included in six consecutive GATLA/GLATHEM protocols, from November 1967 to December 1987. The study was divided in three periods: 1967 to 1975, 1976 to 1982, and 1983 to 1987. Three induction schedules were used during the first two periods, and different maintenance schemes alternating with monthly consolidations were explored; the value of immunotherapy with C. Parvum and androgen therapy with stanozolol was also tested. Protocol 3-AML-83, representing the third period, included a four-week induction phase with vincristine, adriamycin, cytosine-arabinoside, prednisone and 6-mercaptopurine, followed by a consolidation phase with cyclophosphamide, cytosine-arabinoside and 6-mercaptopurine for four weeks. Maintenance phase included daily, oral 6-mercaptopurine, and monthly cytosine-arabinoside, both during two years, and adriamycin every eighth week, for one year. Complete remission rates for the first two periods of therapy were 40% and 55%, whereas that of the last period was 74%. The overall results of the period 1967-1982, showed actuarial duration rates of complete remission, event-free survival and survival, at 60 months, between 2% and 6%, their median duration being of 9, 8 and 10 months respectively. No significant difference was observed between the first two periods or protocols. Protocol 3-AML-83, activated in March 1983, achieved actuarial rates of continuous complete remission, event-free survival, and survival of 51%, 37% and 39% respectively, at 48 months. The difference between the first two periods and the last one was highly significant (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Alternating pulses of vincristine-prednisone with cytarabine-cyclophosphamide versus vincristine-prednisone in the maintenance therapy of acute lymphoblastic leukemia.

From January 1976 to December 1978, 347 children less than or equal to 15 years of age were entered in a collaborative controlled trial which included: induction (vincristine-daunorubicin-prednisone); intensification (cytarabine-cyclophosphamide); CNS prevention (intrathecal methotrexate-dexamethasone, three doses during induction and three weekly doses during the first month of maintenance, followed by one dose every 3 months for 48 months); and maintenance (6-mercaptopurine daily and methotrexate twice weekly with reinforcement pulse doses of either 1.5 mg/m2 X 1 of vincristine plus 40 mg/m2/day X 7 of prednisone [Arm A] or vincristine-prednisone alternating with 50 mg/m2 of cytarabine sc every 12 hours X 10 plus 600 mg/m2 X 1 of cyclophosphamide [Arm B]). Pulses were performed in both arms at 1, 2, 3, 4, and 6 months and every 3 months thereafter. Randomization was stratified according to age and initial wbc count. A total of 89% (310/347) of patients achieved complete remission. Duration of continuous complete remission was evaluated according to prognostic factor groups. At 5 years, 34.5% of patients with good prognosis, 24.8% with intermediate prognosis, and 12.8% with poor prognosis are in continuous complete remission. There is statistical difference between good versus poor prognosis (P less than 0.0005) and intermediate versus poor prognosis (P less than 0.025). Moreover, 5-year survival is 50.9%, 35.2%, and 18.2% in the good-, intermediate-, and poor-prognosis groups, respectively. Duration of continuous complete remission up to the first event (ie, bone marrow, CNS, or other extramedullary relapse, or death in complete remission), according to prognostic groups, did not differ in relation to reinforcement pulses (Arm A or B). We conclude that there was no benefit in alternating pulses of vincristine-prednisone with cyclophosphamide-cytarabine as used in this study.

Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX-DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.

Daunorubicin, vincristine, and prednisone for remission induction in patients with acute lymphoblastic leukemia in relapse.

Patients with recurrent acute lymphoblastic leukemia were treated with daunorubicin (40 mg/m2/week X 4), vincristine (1.5 mg/m2/week X 4), and prednisone (40 mg/m2/day x 28). All of the patients had been treated with the same combination during the first induction treatment. Of 266 patients (221 children and 45 adults) treated in first relapse, 141 (53%) achieved complete remission (CR; 55% of the children and 44% of the adults). Of 61 patients who were re-treated with the same combination after the second relapse, 14 (23%) achieved CR. The difference between second and third CR was statistically significant (P less than 0.0005). The median durations of second and third CR were 8 and 6 weeks, respectively. No significant difference was observed when the duration of CR was compared with the initial wbc count, age at diagnosis, or duration of first CR.

Vindesine, prednisone, and daunomycin in acute lymphoblastic leukemia in relapse.

Patients with resistant or recurrent acute lymphoblastic leukemia were treated with vindesine 3 mg/m2/IV weekly X 4, daunomycin 25 mg/m2/IV weekly X 4, and prednisone 40 mg/m2/PO daily X 28. Seventeen (44%) of 38 evaluable patients achieved complete remission. Fifty-one percent of 31 patients in first relapse achieved complete remission, while only one of five in second or third relapse and neither of two resistant to first induction achieved complete remission. The major toxicity was hematologic. The median duration of complete remission was only 6 weeks and median survival from start of the study, 3 months, with 22% patients remaining alive at 10 months. We conclude that the vindesine, prednisone, and daunomycin combination is no more effective than vincristine, prednisone, and daunomycin in achieving remission of relapsed acute lymphoblastic leukemia patients, and is more toxic than the latter regimen.

Hodgkin's disease in childhood: therapy results in Argentina.

From 1940 to 1977, a total of 152 children aged 15 years or less with the histologic diagnosis of Hodgkin's disease were treated in Argentina. For analysis, these patients were placed into three periods which displayed the most outstanding changes in diagnostic workup and therapy. The periods are as follows: (1) 1940 to 1966 (43 children), (2) 1967 to 1972 (35 children), and (3) 1973 to 1977 (74 children). The patients were treated with extended field radiation therapy and followed by courses of cyclophosphamide-vinblastine-procarbazine-prednisone, with CCNU added (CCVPP) or not added (CVPP) in a randomized trial. The mean age of the whole group was 7.5 years (range 2 to 15 years) and there was a predominance of males (79%). Crude 6-year survival for the three periods were as follows: 1940 to 1966, 34%; 1967 to 1972, 50%; and 1973 to 1977, 79%. We conclude that (1) survival of Hodgkin's disease of childhood has shown a rather marked improvement during the last decade and this progress is probably due to the use of combined multidrug chemotherapy administered under collaborative controlled clinical trials; (2) preliminary evaluation of the results of CVPP and CCVPP therapy shows that the latter combination (CCVPP) neither increases the percent of patients achieving complete remission nor prolongs relapse-survival in Hodgkin's disease of childhood: and (3) all stages of childhood Hodgkin's disease can be successfully managed with multidrug chemotherapy alone.

Case report: hypoparathyroidism and iron storage disease. Treatment with 25-hydroxy-vitamin D3.

A patient in whom hypoparathyroidism developed as a complication of posttransfusional iron storage disease is described. The hypoparathyroidism occurred after more than 15 years of receiving blood transfusions at frequent intervals. In this patient with thalassemia major the serum PTH levels were undetectable. 25-hydroxy-vitamin D3 corrected the hypocalcemia that was resistant to vitamin D2, probably due to the associated liver dysfunction. Other cases reported in the literature are reviewed. It is suggested that hypoparathyroidism occurs more frequently than usually suspected in patients with iron storage disease.

Non-Hodgkin's lymphoma in children: an analysis of 122 cases from Argentina.

One hundred twenty two children with non-Hodgkin's lymphoma were studied from January 1966 to December 1975. The first group (1966-1972) did not receive an uniform treatment. The second group (1973-1975) entered in a G.A.T.L.A. protocol consisting of: vincristine-prednisone plus surgery and/or radiotherapy as induction treatment, craniocervical radiotherapy and intrathecal methotrexate as CNS preventive treatment and anti-leukemia (6-mercaptopurine, methotrexate and vincristine-prednisone pulses) or anti-lymphoma (COPP) treatment as maintenance, in a randomized trial. Comparison of survival of the two groups are as follows: series 1966-1972, 22% and 20% at 12 and 24 months of evolution, respectively, and series 1973-1975, 33% and 26% at 12 and 24 months, respectively. After 2 years of complete remission we have not seen any relapse. We conclude that 1) this disease is highly malignant and must be treated with more intensive chemotherapeutic treatment, and 2) there is no difference between antileukemia or anti-lymphoma maintenance treatment, as yet.