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Notes: Summary Aiming at a high complete remission rate with an intensive induction regimen, 27 patients with advanced breast cancer were given three cycles of VAC chemotherapy consisting of vinde-sine 3 mg/m2 i.v. on days 1 and 12, adriamycin 40 mg/m2 i.v. on days 1 and 12, and cyclophosphamide 200 mg/m2 p.o. on days 3–6 and 14–17 together with medroxyprogesterone acetate (MPA) 1,500 mg p.o. daily during the induction phase and 1,000 mg p.o. thereafter until relapse. These VAC double cycles were repeated twice with 3-weekly intervals for a total induction period of 15 weeks. In responders, including no change, the chemotherapy was discontinued thereafter, and the patients were observed until relapse with a maintenance therapy of MPA 1,000 mg p.o. daily. A complete remission (CR) was achieved in 8 (29.6%) and a partial remission (PR) in 13 (48.2%) of the 27 patients (CR + PR 77.8%). A no change (NC) status was found in 6 patients (22.2%). There were no nonresponders. The median duration of the CR was 20 (5–42) months with two patients still in CR at 33 and 36 months, of the PR 8.3 (4–13.5) months, and of the NC 6.7 (2–13) months. The treatment was tolerated without life-threatening toxicity or interval prolongation by all patients. No dose-limiting cardiac toxicity was observed in these patients regularly controlled by left ventricular ejection fraction (LVEF). The high response rate of this intensive induction regimen warrants further investigation. Complete remission was achieved only in patients without previous chemotherapy, with marked tumor regression after the first chemotherapy cycle and when there was no extensive bone involvement.

Notes: Summary In 68 patients with metastatic breast cancer a follow-up study was performed to correlate circulating immune complexes (CIC) as detected by the C1q binding assay and the Raji cell radio immunoassay with the state of disease. Clinical examinations and determinations of CIC were carried out all four to eight weeks over at least six months. 19 patients were positive for CIC in the C1q binding assay and 12 in the Raji cell radio-immunoassay. There was no correlation between the results of both tests. In comparison 26 patients out of 68 with rheumatoid arthritis were positive in the C1q binding assay and 32 in the Raji cell assay. In these patients the results of both tests correlated significantly. There was only in a few cases of metastatic breast cancer a positive correlation between levels of CIC and changes of tumor burden. Furthermore, CIC did not prove to be of prognostic value.

Notes: Summary Both medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are effective in the treatment of metastatic breast cancer. Although the dose-dependent mode of actions of MPA have been extensively clarified, there is still some uncertainty regarding the mode of actions and dosage of MA. Thirty-three patients with metastatic breast cancer were treated with various dosages of MA under a phase-II study. Eight patients were given 200 mg, 9×400 mg, 10×600 mg and 6×800 mg MA daily per os. The LH, FSH, TBI, T3, T4, TSH, ACTH, aldosterone, testosterone, prolactin and cortisol levels were determined regularly during treatment to enable the investigation of the pharmacodynamics of MA. A complete remission was achieved in two patients, a partial remission in seven patients and there was no change in eight patients (total responder rate 51.5%). The clinical and endocrine changes therefore suggest that the dose-dependent mode of actions of MPA and MA are identical. Equivalent dosages of MPA are 1000–1500 mg per os and of MA 160–200 mg. Furthermore, similar relationships between the endocrine changes and remission behaviour of MA and MPA have been observed. Persisting tumour remissions are inevitable under cortisol suppression and normal prolactin, aldosterone and ACTH levels.

Notes: Summary The diagnostic validity of serial CEA determinations in metastatic breast cancer was investigated. First, the CEA values within 8 weeks after start of therapy were correlated with the response to therapy. Second, the CEA levels were used to predict progression after remission or stable disease. These investigations were performed in 150 patients with advanced breast cancer who had clinical follow-ups and serial CEA determinations every one to three months. CEA was not useful for monitoring response to therapy (sensitivity 63%, specifity 58%) or prediction of relapse (sensitivity 61%, specifity 82%) if CEA levels were correlated with clinical course in all patients. However, diagnostic validity of CEA was achieved if the patients were selected and appropriate definitions of significant changes in CEA used. Thus, 83% of the responders (sensitivity) could be identified by a significant decrease of CEA titers in patients with CEA levels of ≧10 ng/ml. A decrease of more than 10% of pretreatment levels during the first 4–8 weeks after start of therapy proved to be the appropriate definition of a significant decrease of CEA titers. However, 32% of the non-responders were misclassified as responders (unspecifity) using these criteria. The positive predictive value of a significant decrease of CEA for response to therapy was 72% (prevalence 45%), the negative predictive value 82% (prevalence 55%). Rising CEA titers specifically predicted progression of disease in patients with remission or stable disease. However, an appropriate sensitivity (86%) was achieved only in patients with baseline CEA levels of ≧5 ng/ml. The selection criteria described applied to one-third of the patients in the present study. Prospective studies based on these results have to show whether the definitions used can be generalized and are to be recommended for clinical practice.

Notes: Summary Based upon preliminary observations that tumor response to MPA was correlated to cortisol suppression 42 patients were treated with MPA at different dose levels. 1 500 mg MPA p.o. almost completely suppressed endogenous cortisol production in 23 out of 23 patients. Consequently, 51 patients with advanced stage metastatic breast cancer were treated with Medroxyprogesteroneacetate (HD-MAP) at a dosage of 1 500 mg p.o. daily or 500 mg i.m. on 5 days per week. There were 5 complete and 7 partical remissions, 23 patients with no change and 10 with progressive disease. 7 patients were not evaluable. Clinical results correlated to plasma cortisol and prolactin blood levels bot not to LH, FSH, TSH, TBI, T3, T4, ACTH and aldosterone measurements. There was no patient with relapse and suppressed cortisol or normal prolactin measurements. The development of pituituary resistance to MPA is suggested. HD-MPA was equally effective in estrogen and/or progesterone receptor positive as in receptor negative patients. It is proposed that cortisol and prolactin determinations are useful to monitor for effective MPA treatment and the early detection of MPA resistance.

Notes: Summary The capability of breast cancer to secrete CEA might have biological significance. In 105 patients with metastatic breast cancer serial CEA determinations and clinical follow-up data were available during progression of disease up to death. In this series, 39 patients (37%) had constantly low CEA levels (〈10 ng/ml), whereas 66 patients (63%) showed CEA values exceeding 10 ng/ml with progression. The patients with low CEA levels had significantly shorter median survival times (P=0.001) after mastectomy (39 versus 65 months) and after recurrence (18 versus 28 months) than the patients with high CEA levels. This difference was due first to a poor-risk group of 13 patients with rapidly disseminating tumors, very short survival (〈12 months), and low CEA levels. Secondly, there were more patients with pulmonary involvement and unfavorable prognosis and fewer patients with osseous metastases and long survival in the low-CEA group. In conclusion, there might be a subtype of breast cancer with rapid progression and low CEA secretion. This clinical observation has to be confirmed by histological grading and CEA staining of these tumors.

Notes: The metabolism of deutrated cortisol (9,12,12,-2H)cortisol, (2H3-F) was compared to that of radioactive cortisol (3H2-F) and natural cortisol, when these three compounds were administered simultaneously to an adrenalectomized piglet. The relative isotope dilution of tritium was determined from the specific activities of the main urinary neutral cortisol metabolites, tetrahydrocortisone (THE) and tetrahydrocortisol (THF), normalized to that of the cortisol mixture administered. To obtain a comparison of the isotope dilution of deuterium in the metabolites THE and THF to that in the cortisol mixture, the three steroids were converted to the common oxidation product 11-oxo-aetiocholanolone, and deivatized to the methoxime-tert-butyl-dimethylsilyl ether. The relative 2H-isotope dilution then was measured by gas chromatography/mass spectrometry. It was found that the specific activity of THE in the cumulative urine collections was similar to that of the cortisol mixture administered; the two-day value was, however, less. The specific activity of THF was slightly but significantly smaller than 1 (∼0.9) at all times. The relative 2H-isotope dilution in THE was slightly but significantly larger than one (∼1.1) at all times, whereas that in the THF was larger than 1.0 at 9 and 32 h or equal to 1.0 at 20 and 47 h of urine collection. When comparing the metabolism of the two tracer cortisol species the quotient of the 3H- and the 2H-isotope dilutions in THE and THF was smaller than 1.0. It can be concluded that (2H3)cortisol may be used for the determination of the cortisol production rate.

Notes: An isotope dilution mass spectrometric method to determine the urinary cortisol production rate (CPR) in babies and children is described. The method uses stable isotopically labelled (1,2,3,4-13C)cortisol. The tracer is intravenously administered to the patient and urine is collected for the following three days. Following extraction, enzymic hydrolysis, purification and isolation by high-performance liquid chromatography (HPLC) the urinary cortisol metabolites tetrahydrocortisone, tetrahydrocortisol, α- and β-cortolone are separately oxidized to the common product, 11-oxo-aetiocholanolone. The methyl oxime tert-butyldimethylsilyl ether derivative (MO TBDMS) was analysed by gas chromatography mass spectrometry. Quantification of the isotope enrichment was carried out by selected ion monitoring of the base fragment ion at m/z 344[M-103]+ for unlabelled, and at m/z 348 for labelled 11-oxo-aetiocholanolone. HPLC isolation of the metabolites together with the oxidation step allowed very small isotope enrichments, sometimes down to 0.1% (1:1000), to be reliably measured against a linear calibration graph containing 0 to 1% (13C4) enrichments. The standards for the calibration graph were synthesized from mixtures of labelled (13C4) cortisol and natural cortisol, and the calibration graph was prepared each time samples were measured. The long term instrumental precision of the isotope dilution analyses was 0.91% for a derivatized sample containing a (13C4) enrichment of 0.5% (measured on six different days over seven months). The coefficient of variation of the complete procedure for the four cortisol metabolites was between 1.17 and 2.14%. The clinical applicability of the method is demonstrated by presenting the results of a CPR determination in a patient.

Notes: Adrenalectomized piglets were intravenously administered a mixture of (13C4)cortisol and (3H)cortisol and natural cortisol to determine if the two tracers are metabolized identically to natural cortisol. Urine was collected after 0.5, 1.0, 1.5 and 2.0 days and the isotope dilution was measured in the four major urinary cortisol metabolites, namely tetrahydrocortisone (THE), tetrahydrocortisol THF), α-and β-cortolone in the cumulative urines. In contrast to other studies, because of the sensitivity of the method used to measure the 13C4 enrichment, non-cumulative urine collections were also analysed. Quantification of the 13C4 isotope enrichement was carried out by gas chromatography/mass spectrometry with selected ion monitoring. The specific activities of the metabolites from the cumulative urine collections were determined by high-performance liquid chromatography and scintillation counting. Small secondary isotope effects seemed to occur during the metabolism of (13C4)cortisol, as a decrease in isotope enrichment in all four metabolites was measured. These effects were easily observed with α-and β-cortolone isolated from the cumulative urine collections; the enrichment decreased by 19% and 14%, respectively. The lowering in isotope dilution in THE observed in the 2.0 day cumulative urine collection in piglets 1 and 2 were 4% and 3%, respectively. A lowering in isotope dilution in THF in the 2.0 day cumulative urine collection could be observed in piglet 2, namely 7%, but no change in isotope dilution could be seen in piglet 1. These secondary isotope effects could only be observed in the 2 days cumulative urine, and not in the cumulative urines collected over shorter times. The non-cumulative urines collected at half-day periods showed a significant decrease in isotope dilution in THE and THF isolated from the urine collected after 1 day. No statistically significant isotope effects were observed with the metabolism of (3H)cortisol, except at 0.5 day when the specific activity in the cortolones was lower and that in THF was higher. However, at 0.5 day with THE and 1.0 day with THF and the cortolones the specific activities remained approximately 6% higher than that administered in the cortisol. Secondary isotope effects with tritiated cortisol may have occurred but because of the relatively large imprecision of the measurement (SD = 3-4% with THE and THF and the cortolones (SD ≈ 8) compared to the measurements of the 13C4 enrichment (SD ≈ 2%) these effects could not statistically be proven. The 13C enrichment: specific activity ratios of THE and THF isolated from the cumulative urines further illustrated that the metabolites were more preferentially enriched in 3H than in 13C. The apparent biological secondary isotope effects observed in the cumlative 2 day urine collections are smaller for (13C4)cortisol than for (3H2)cortisol. If these isotope effects also occur in man, then the 13C4-labelled tracer would be better than the 3H tracer for measuring the urinary cortisol production rate.