Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients. clinical outcomes and oncologists' preferences.

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

Modulation of the IL-2 production defect in vitro in Graves' disease.

IL-2 production by mitogen-induced peripheral blood mononuclear cells was reported to be reduced in several autoimmune diseases, including Graves' disease (GD). This production defect in hyperthyroid GD was restored to normal by antithyroid drug therapy or during remission. However, its underlying mechanism and role in the autoimmune process are still uncertain. The present study was undertaken in order to screen the in vitro IL-2 generating system for putative factors responsible for its failure, and to see to what extent this was reversible. Thyroid hormone or antithyroid drugs had no effect on IL-2 production in vitro. Cultures were found to be free of soluble inhibitors of IL-2 production or action. IL-1 deficiency as a cause of the IL-2 defect was ruled out; rather, Graves' adherent cells were found to be activated in being capable of secreting large amounts of IL-1 and prostaglandin E2 (PGE2). The latter was not found to be responsible for the decreased IL-2 production. IL-2 production by Graves' mononuclears was completely restored to normal by: (i) adherent cell depletion, irradiation or substitution with normal adherent cells; (ii) preincubation of mononuclears for 24-72 h before mitogen stimulation; (iii) the synergistic action of a phorbol ester and a calcium ionophore. These data indicate that inhibition by activated adherent cells accounts for the in vitro IL-2 production defect in GD. This inhibition is not mediated by soluble factors, but probably through direct interaction with the producing cells, and is reversible in rested cultures or through a bypassed signal transduction.

Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment.

In 58 breast cancer patients with meningeal carcinomatosis (MC) pretreatment characteristics, clinical course, and response to treatment were evaluated. Forty-four patients were uniformly treated with intraventricular chemotherapy. Fourteen patients did not receive intraventricular treatment. In the intraventricularly treated group the median survival was 12 weeks. Multivariate analysis of the pretreatment characteristics of the intraventricularly treated patients demonstrated a prognostic significance with respect to survival for age older than 55 years, lung metastases, cranial nerve involvement, cerebrospinal fluid (CSF) glucose less than 2.5 mmol/l, and CSF protein 0.51 to 1.0 g/l. Based on the significance of these predicting factors a prognostic index (PI) identified four groups of patients with a median survival of 43 weeks, 22 weeks, 11 weeks, and 3 weeks, respectively. After 6 weeks of intraventricular treatment 22 patients showed a neurologic improvement or stabilization, and nine patients showed a worsening of the neurologic signs, whereas 13 patients (30%) had already died. The responders had a median additional survival of 5 months versus 1 month for nonresponders. No relation was found between survival and intensity of the intraventricular treatment after the first 6 weeks of treatment. Almost all long survivors had also received systemic treatment for systemic disease, whereas most patients who died within 6 months did not receive systemic therapy. Radiation therapy had no influence on the survival time. Early death due to the intensive treatment occurred in three patients. In 11 of the 17 patients who survived more than 4 months an often seriously debilitating late neurotoxicity developed. The survival curve of the nonintraventricularly treated patients appeared to be essentially the same as the curve of the intraventricularly treated patients. Using the same PI the predicted survival time was also the same as in the intraventricularly treated group. It is concluded that survival in MC from breast carcinoma may be more dependent on some pretreatment characteristics than on treatment intensity. On the basis of these pretreatment characteristics the survival time seems to be predictable. Finally, late neurotoxicity due to aggressive treatment leads to impairment of the quality of life in more than 50% of the long survivors. The exact value of intraventricular and systemic therapy in patients with MC still has to be determined.

"Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III Trial (10808).

The "classical" CMF (cyclophosphamide/methotrexate/5-fluorouracil) schedule was compared with a modified 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer, as concern had arisen as to whether the classical schedule was the optimal way to give these drugs. The response rate with classical CMF was 48% compared with 29% for intravenous CMF (P = 0.003). Response duration was similar at 11 months, but survival longer for the classical schedule (17 versus 12 months, P = 0.016). We conclude that classical CMF is the superior regimen and attribute this to the higher dose intensity achieved.

Alcohol policies in The Netherlands a three-pronged attack.

The Dutch will not readily accept restrictions on their freedom to drink alcohol. The government therefore relies on a mass education campaign urging moderation, the efficient detection and treatment of alcoholics, and the regulation of advertising.

Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy. An EORTC Breast Cancer Co-operative Group Trial (10792).

Patients with locally advanced carcinoma of the breast were randomized to receive either radiotherapy alone, radiotherapy + endocrine therapy, radiotherapy + chemotherapy or radiotherapy + endocrine therapy + chemotherapy. In 363 evaluable patients, time to first progression was delayed significantly by both endocrine treatment and chemotherapy, the greatest effect being achieved by the combination of endocrine treatment and chemotherapy. This effect was almost entirely due to a major effect of systemic treatment on time to loco-regional progression, for which the result is highly significant, rather than time to distant metastasis in which only a non-significant trend was observed. For survival, a trend was seen in favour of the combination of hormone treatment and chemotherapy, but this effect did not achieve statistical significance. This trial suggests that current endocrine and cytotoxic treatments are only of marginal value in improving the prognosis in locally advanced breast cancer.

Dutch policy on the management of drug-related problems.

It is argued that the drug abuse problem should not be primarily seen as a problem of police and justice. It is essentially a manner of health. The Dutch acknowledge that the international repressive, prohibitive approach leads to unintentional negative side-effects, both for the individual and for society. They try to avoid a situation in which consumers of cannabis suffer more damage from the criminal proceedings than from the use of the drug itself. They opt rather for a realistic and practical approach to the drug problem than for a moralistic and over-dramatized one. The Dutch alternative is the normalization of the drug problem, as a pragmatic compromise between two extreme options: an intensified war on drugs and legalization. The implications of the normalization approach for the prevention and treatment policies are discussed: AIDS-prevention, harm reduction instead of detoxification and de-mystification. It is suggested that the policy of normalization is rather successful and does not produce an increase of drug use.

Production of and response to interleukin-2 in Graves' disease.

Interleukin-2 is a lymphokine which is believed to play a central role in the regulation of the immune response. The production of and response to interleukin-2 were determined in hyperthyroid Graves' patients together with thyroid function and serum thyrotropin receptor antibody, a marker of autoimmune activity. Interleukin-2 production by mitogen-induced peripheral blood mononuclears was markedly low in 24 of 29 patients when compared to controls. Five patients in remission had normal values. In nine patients followed during antithyroid drug therapy, interleukin-2 production returned gradually to normal levels within 4-6 months. This rise and the concomitant decrease in serum thyrotropin receptor antibody correlated with the decline in the free thyroxin index. Antithyroid drugs and triiodothyronine had no effect on interleukin-2 production in vitro. Mitogen-activated mononuclears from hyperthyroid Graves' patients did not proliferate as well as the controls in response to interleukin-2. However, seven patients treated with antithyroid drugs and three in remission responded normally. Flow cytometry using anti-Tac antibody revealed that the interleukin-2 receptor density on mononuclears from five patients was low. This parameter was normal in treated patients and those in remission. We conclude that the production of and response to interleukin-2 by peripheral blood mononuclears from hyperthyroid Graves' patients are poor, the latter being due to impaired receptor expression. Both aberrations are restored to normal by antithyroid drug therapy or in remission. The relative roles of the autoimmune process and thyroid function in modulating the interleukin-2 pathway and the question of whether antithyroid drugs act directly or through thyroid inhibition remain to be clarified.

The role of I-131-MIBG in the diagnosis and therapy of carcinoids.

The successful use of 131I-MIBG for the diagnosis and treatment of pheochromocytoma and neuroblastoma has led to its application in patients with carcinoid, another neural crest tumor. The present report describes the scintigraphic findings, in correlation with clinical and biochemical parameters, in 20 patients with histologically proven carcinoids. 131I-MIBG total body scintigraphy was positive in 12 and equivocal in 1 of 19 patients with metastases. The necessity of delayed imaging and the possible advantage of single photon emission tomography for the detection of this tumor are emphasized. The results of 131I-MIBG treatment in five patients with progressive carcinoid metastases are discussed. It is concluded that 131I-MIBG has a role in the work up of patients with proven carcinoid and can be used for palliative treatment of this tumor.

Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study.

UNLABELLED: Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together, p = 0.11. Local recurrence (LR) was observed in 24 of the 86 patients (28%) who had reached complete remission (CR). LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. In arm III, the CR rate after 4 cycles AV plus CMF and RT hardly changed after another 8 cycles of chemotherapy. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results, p = 0.04. IN CONCLUSION: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.