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Purpose: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens., Patients and Methods: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months., Results: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain., Conclusion: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

131I treatment is an effective alternative to surgery in patients with a large, (non-)toxic, compressive goiter. Late development of hyperthyroidism after 131I therapy for nontoxic nodular goiter is considered rare. We have seen this complication in 3 of approximately 80 patients treated with radioiodine for volume reduction of a large, multinodular goiter. Three women, aged 60 to 71 years, had large, multinodular goiters causing tracheal compression. They were clinically euthyroid before 131I therapy and had normal free thyroxine (FT4) levels. Serum thyroid-stimulating hormone (TSH) levels were normal in 2 patients and undetectable in 1 patient. Patients 1 and 2 received a single dose of 86 and 48 mCi 131I, respectively. Patient 3 received 20 mCi 131I twice (interval 1 month). Clinical and biochemical thyrotoxicosis with high thyroid radioactive iodide uptake (RAIU) developed 10, 6, and 3 months after 131I therapy, respectively, although at control visits 1 to 3 months earlier, serum TSH and FT4 levels were normal. Thyrotoxicosis responded well to methimazole in all three patients. The late occurrence of thyrotoxicosis, high RAIU, and good response to methimazole argue against thyroiditis as the cause of thyrotoxicosis. Serum levels of TSH receptor antibodies, which were undetectable before therapy (patients 1 and 2), were clearly elevated in all three patients during thyrotoxicosis. This is in favor of autoimmune hyperthyroidism as the cause of thyrotoxicosis. These cases illustrate that severe autoimmune hyperthyroidism may occur several months after radioiodine treatment for nontoxic, multinodular goiter. Information about symptoms of hyperthyroidism and regular control visits in the first year after therapy are important in these patients.

The case history is presented of a woman who developed serious liver injury while taking 36 mg tizanidine daily. Other causes of hepatic injury were excluded. Symptoms resolved after discontinuation of tizanidine, and the liver enzyme levels were nearly normal 6 weeks after discontinuation of the drug. Rechallenge with 4 mg tizanidine caused a relapse. The temporal relationship between the symptoms and liver enzyme elevations, the absence of other potential causes, and the reaction to rechallenge, strongly implicate tizanidine as the cause of hepatic injury. As we are not aware of similar case histories, this seems to be the first reported case of tizanidine-induced hepatic injury.

The effects of granulocyte colony-stimulating factor (G-CSF) on total dose and dose intensity of standard oral adjuvant CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy were studied in premenopausal patients with node-positive breast cancer. Treatment consisted of standard CMF and locoregional radiotherapy (on indication). G-CSF was administered if the leukocyte count recovery was insufficient. Fifty-one patients required no G-CSF ("no cytopenia'), and 50 patients received G-CSF ("G-CSF). Twenty-two patients, however, received no G-CSF support despite insufficient leukocyte recovery ("control'). Following G-CSF, leukocyte recovery was adequate in 83% of the chemotherapy cycles. The proportion of the patients who had a dose intensity > or = 85% was 90% in the "no cytopenia' group, 74% in the "G-CSF' group, and 45% in "control' group (p < 0.05). Leukocyte recovery was adequate in 87% of the chemotherapy cycles in the patients who received radiotherapy as compared with 92% of those in the patients without radiotherapy (p < 0.05). In conclusion an adequate leukocyte recovery after G-CSF was found in 83% of all chemotherapy cycles. The dose intensity of the G-CSF group was higher as compared with controls. The impact of radiotherapy on hematological recovery was significant, but not dependent on G-CSF.

A simple cytological scoring system was evaluated as a method of predicting histological grade and disease-free survival in 79 patients with primary breast cancer. The mitotic activity index and oestrogen receptor status were also assessed for their predictive value. The concordance between cytological scores and histological grades was good (80%) for low-grade lesions, but poor (45%) for high-grade lesions. Similar results were found using the mitotic activity index as a prognostic indicator. Cytological grading was not found to be an independent prognostic indicator after a median follow up of 8 years.

A case of a 69-year-old man with an extra-adrenal malignant phaeochromocytoma is described. Sputum cytology revealed metastatic cells, which have not been reported previously in malignant phaeochromocytoma. This case is also remarkable for the short duration of disease, rapid progression and extensive spread of metastases, the radiological aspect of metastatic lesions shown by chest X-ray, hypercalcaemia and extremely high levels of circulating catecholamines and urinary metabolites.

A patient is presented with signs mimicking deep venous thrombosis of the leg, which proved to be compression of the femoral vein, without thrombosis, caused by a large cyst from the adjacent hip joint. Clinical presentation, diagnostic imaging procedures and therapy are presented with a review of the literature.

Serum levels of cortisol (C), androstenedione (A), dehydroepiandrosterone (D), estrone (E1) and estradiol (E2) were chosen as parameters to compare the bioavailability of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in postmenopausal patients with advanced breast cancer. In 36 patients randomized to MPA, the levels of A (13% vs. 19%) and C (6% vs. 8%) were slightly lower than in 36 patients on MA, but D-levels (68% vs. 59%) and E1 or E2, were similar. The correlation between baseline C and A disappeared during treatment. Treatment levels of E1 and E2 were correlated. There was no correlation between individual drug levels and any steroid, indicating a maximal suppression. After ingestion of a single dose of MA or MPA, peak levels were found after 2-3 h for MA and 3-4 h for MPA. Four hours after ingestion, the levels of A and C were similar, 40-60% of baseline values, while D levels remained unaltered. Doubling the dose of either drug did not enhance hormone suppression, indicating that the drug dosage is maximally suppressive. In conclusion, although the median serum MA levels are double those of MPA, suppression of A, C and D is usually similar, with corresponding estrogen levels, demonstrating a comparable and maximal bioavailability. Higher dosages of MA or MPA will not increase their pharmacological effects any further.

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 X 80 mg p.o. or MPA 2 X 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.

We analyzed the relapse rates of hyperthyroidism and prevalence rates of hypothyroidism after partial thyroidectomy and radio-iodine therapy in patients with Graves' disease and toxic multinodular goitre. In achieving euthyroidism, partial thyroidectomy was more effective in patients with Graves' disease (P less than 0.02). In patients with toxic multinodular goitre, radio-iodine therapy was more successful (P less than 0.05). Relapse of hyperthyroidism occurred more often in the radio-iodine group (P less than 0.02), mainly in patients with Graves' disease, and was seen sooner after radio-iodine therapy than after surgery (P less than 0.0001). Patients with toxic multinodular goitre, developed hypothyroidism more often after partial thyroidectomy than after 131I (P less than 0.01). In contrast, in patients with Graves' disease, hypothyroidism occurred more often after radio-iodine therapy than in the toxic multinodular goitre group (P less than 0.02). We conclude that the cause of hyperthyroidism strongly influences the efficacy of the therapeutic regimen.

In a prospective randomized multicenter study in previously untreated postmenopausal patients with advanced breast cancer, the response to treatment with oral medroxyprogesterone acetate (MPA) 300 mg three times daily was compared with tamoxifen (TAM) 20 mg twice daily. Of 61 patients treated with MPA, 27 (44%) had a partial or complete remission, 6 showed no change, and 28 had progressive disease. Of 68 patients treated with TAM, 24 (35%) showed a remission, 15 no change, and 29 progression. The difference in response rate is not significant. However, 11 of 25 patients with osseous metastases as predominant site, responded to MPA and 7 of 31 to TAM (P = 0.05). Moreover, in patients older than age 70 years, 13 of 26 responded to MPA and 6 of 31 to TAM (P less than 0.05). Median duration of remission of all patients in the MPA arm was 17 months and in the TAM arm, 23 months (not significant). Median survival was 20 months for MPA and 26 months for TAM (not significant). After cross-over from TAM to MPA 8 of 31 patients responded and after cross-over from MPA to TAM, no response was seen in 27 patients. These data indicate that the response rate and duration to MPA and TAM are comparable, except in patients with osseous metastases and in patients older than age 70 years. MPA has more side effects, but seems to be more effective after cross-over, and may thus be reserved for second-line treatment.