J.S. Malpas

Cyclical combination chemotherapy and gonadal function. Retrospective study in males.

The effect of cyclical chemotherapy on fertility and gonadal function was investigated in seventy-four male patients who had been treated for advanced Hodgkins disease. All patients were azoospermic after therapy, and, with a median follow-up period of 27 months (range 1--62 months), only four patients have regained spermatogenesis. Testicular biopsy showed an absence of germinal epithelium without other gross architectural changes. Despite this high degree of infertility, 60% of patients were practising contraception. A decline in libido and sexual performance with frequent long periods of sexual inactivity was noted by most men during therapy. Although some recovery was apparent once therapy was stopped, this was incomplete in approximately half of the patients. Follicle-stimulating-hormone levels were consistently raised after therapy at all periods of study. Median luteinising-hormone levels were at, or just above, the upper limit of normal, and median testosterone levels were normal. Increased prolactin levels were noted in 42% of patients, of whom about a half had an identifiable cause for hyperprolactinaemia. Return of spermatogenesis could not be predicted by serial hormone assessment. Because of the guaranteed infertility and the low frequency and unpredictability of recovery of spermatogenesis, sperm storage should be available for male patients undergoing cytotoxic therapy, since most of these patients may enjoy prolonged survival. Hormone-replacement therapy will usually be unnecessary. However, the probability of major changes in libido and sexual performance should be discussed with patients so that additional stress can be avoided. Contraceptive advice should be available to those who require it.

INTENSIVE TREATMENT OF MULTIPLE MYELOMA AND CRITERIA FOR COMPLETE REMISSION

50 previously untreated patients with multiple myeloma received two-phase treatment: repeated cycles of 4 day infusion with vincristine, doxorubicin, and methylprednisolone (VAMP) followed by high-dose melphalan (HDM), with autologous bone marrow transplantation where possible. The overall response rate was 74% (37/50), with 25 patients (50%) achieving complete haematological and biochemical remission. These remissions were associated with a good quality of life as measured by performance status, pain grade, and the reversal of humoral immunosuppression. 6 patients died during the VAMP phase and there was 1 death related to HDM. The achievement of complete remission, as defined here, in such a high proportion of patients is exceptional and may represent a useful advance in the management of myeloma.

USE OF PANELS OF MONOCLONAL ANTIBODIES IN THE DIFFERENTIAL DIAGNOSIS OF NEUROBLASTOMA AND LYMPHOBLASTIC DISORDERS

Panels of monoclonal antibodies offer a rapid and accurate adjunct to conventional techniques in the diagnosis of neuroblastoma, leukaemia, and lymphoblastic lymphoma. Heterogeneity of antigen expression is observed within a tumour type, and therefore a panel of reagents should be used for each malignancy investigated. Eight monoclonal antibodies which bind to neuroblastoma but not to normal bone marrow and five which bind to leukaemic and lymphoma cells but not to neuroblastoma have been selected for indirect-immunofluorescence testing of bone-marrow aspirates, frozen sections of tumours, and cells from malignant effusions. With this technique a confident diagnosis can be made within 2 h. Profiles of antibodies binding to tumour cells have been used to establish a definitive diagnosis in cases where conventional techniques have proved inadequate.

High-dose cytosine arabinoside: response to therapy in acute leukaemia and non-Hodgkin's lymphoma

SummaryTwenty-six patients with acute leukaemia and 14 with high-grade lymphoma received cytosine arabinoside (ara-C) at a twice daily dose of 2 g/m2 administered as a 3-h infusion. Thirty-four patients received 12 doses and six electively received four doses only. Complete remission was achieved in six of seven patients with acute myelogenous leukaemia (AML), one of two evaluable patients with blast crisis of chronic myeloid leukaemia and three of eight patients with acute lymphoblastic leukaemia (ALL). Three further patients with ALL had only minimal bone marrow infiltration after one cycle, toxicity precluding administration of a second. Three patients with AML who received four doses only showed no evidence of response. Four of 14 patients with lymphoma who received 12 doses, entered complete remission. Five additional patients died with minimal residual disease whilst severely neutropenic. A complete and a partial response were seen in two patients with immunoblastic and centrocytic lymphoma respectively who received four doses. These results confirm the activity of high-dose ara-C in patients with AML and suggest that it may also be a potentially useful agent in ALL and high-grade lymphoma, especially as the incidence of CNS toxicity is lower than that reported at higher doses.

Liver damage in children with acute leukaemia and non-Hodgkin's lymphoma on oral maintenance chemotherapy

SummaryEight of 36 children receiving maintenance chemotherapy for acute lymphoblastic leukaemia or non-Hodgkins lymphoma had liver biopsies on the basis of clinical abnormalities and/or elevated serum enzyme levels. Six biopsies were abnormal, including one in a boy with spider naevi who showed micronodular cirrhosis; he appeared to retain methotrexate in the blood for a prolonged period and his SGOT level did not return to normal for 19 months after maintenance chemotherapy was discontinued. The five other abnormal biopsies showed minor changes in the portal tracts. The six children with abnormal liver histology showed a wide variation in their early handling of an oral methotrexate dose.There was a statistically significant rise in mean SGOT and alkaline phosphatase during treatment, but the wide scatter in values precluded their use as accurate indicators of liver damage in these children.

Hodgkin's disease occurring during acute leukaemia in remission.

Three patients with acute lymphoblastic leukaemia are reported in whom Hodgkins disease developed during chemotherapy-maintained remission. This association has been reported only once before. The pathogenesis of the Hodgkins disease in these patients is discussed, including the possible role of anti-leukaemic therapy.

Treatment of acute leukaemia with m-AMSA in combination with cytosine arabinoside

SummaryA series of 46 patients with acute leukaemia were treated with amsacrine (m-AMSA) and cytosine arabinoside (ara-C). Complete remission (CR) was achieved in 15 of 38 (40%) patients with acute myelogenous leukaemia (AML) and 4 of 8 (50%) patients with acute lymphoblastic leukaemia (ALL). The CR rate was significantly higher (P(0.05) for the younger, previously treated patients with AML (9/16) than for the older previously untreated ones (6/22), because of higher treatment mortality in the latter group.Myelosuppression was prolonged and profound. Major nonhaematological toxicity affected the gastrointestinal tract (nausea, vomiting, mucositis, bleeding and ileus associated with severe diarrhoea). Many patients also developed reversible hepatic dysfunction and two elderly patients died of cardiac arrhythmia.Further trials of this combination are justified in patients with relapsed or resistant leukaemia, but for older patients dose reduction is recommended.

Combination chemotherapy for advanced non-Hodgkin's lymphoma of unfavourable histology

SummaryThirty previously untreated adults with diffuse histiocytic and diffuse undifferentiated lymphoma were treated with a combination of adriamycin, vincristine, prednisolone, and l-asparaginase. Complete remission was achieved in 11 out of 12 cases with stage III and 7 out of 18 cases with stage IV disease (P<0.005). Bone marrow infiltration, clinical central nervous system involvement, and massive intra-abdominal disease all influenced the prognosis adversely. Complete remission was followed by cranial irradiation and intrathecal methotrexate, and maintained with weekly cyclophosphamide and methotrexate and daily 6-mercaptopurine. The duration of remission was significantly longer for patients with stage III disease (the median of which has not been reached), than for patients with stage IV disease (P=0.007). Survival was significantly longer for patients in whom complete remission was achieved than for those in whom it was not (P=0.001), and also for patients with stage III than for those with stage IV disease (P=0.02).

COMPARISON OF BETHANIDINE, α-METHYLDOPA, AND RESERPINE IN ESSENTIAL HYPERTENSION

Abstract A controlled double-blind trial was carried out in 60 matched patients with essential hypertension in which bethanidine, α-methyldopa, and reserpine, each given in varying doses together with a thiazide diuretic, were compared over a three-month treatment period. The drugs were similar in their antihypertensive effects; reserpine produced the smallest incidence of side-effects.

Phase I and II study of AMSA in childhood tumours

SummaryTwenty-nine children with tumours that had failed to respond to conventional therapy have been treated with AMSA. There were 16 patients with haematological malignancies in whom treatment was initiated at 25 mg/m2 for 3 days, increasing to 150 mg/m2 for 5 days. There were one complete and four partial remissions in these patients, all of whom had received at least 500 mg AMSA/m2. Thirteen children with solid tumours were treated. They received single doses of 120 mg/m2 initially, increasing to 100 mg/m2 for 5 days. No complete or partial responses occurred, but some antitumour activity was noted in neuroblastoma and retinoblastoma. Dose-related severe bone marrow toxicity occurred, but gastrointestinal and other toxicity was mild. An additional patient with T cell lymphoma, who received AMSA prior to a successful autologous bone marrow transplant, is described.AMSA is an active drug in childhood leukaemia. Further studies at the maximum tolerated dose are needed to assess enough patients with any single solid tumour type. In particular, the response of neuroblastoma warrants further study. Investigation of the use of AMSA either prior to bone marrow transplantation in leukaemia or in association with autologous marrow transplant in neuroblastoma and other solid tumours may be of value.