Docetaxel in 253 previously treated patients with progressive locally advanced or metastatic breast cancer: results of a compassionate use program in The Netherlands.

The aims of this study were to evaluate the efficacy and safety of docetaxel (Taxotere) in patients with progressive locally advanced or metastatic breast cancer, previously treated with at least one chemotherapy regimen, and the effect of the number of previous chemotherapy lines on response rate, progression-free survival and overall survival. Two-hundred and fifty-three patients from 10 hospitals in The Netherlands received docetaxel as part of a compassionate use program. The majority had received prior anthracycline-containing chemotherapy (84.2%). The recommended starting dose was 100 mg/m2 i.v. every 3 weeks. All patients received corticosteroid premedication. Two-hundred and thirty patients were evaluable for response. The overall response rates (ORR) to docetaxel when used as second-, third- or fourth-line treatment were, respectively, 40.2, 26.0 and 34.6% (p value 0.30). The median progression-free survival for this population was 4.9 months and the median overall survival of the whole group was 8.5 months, and both were not related to the number of previous chemotherapy regimens (p value, respectively, 0.71 and 0.16). The toxicity of docetaxel was manageable and neutropenia was the most frequently noted toxicity. This study confirms that docetaxel is an active cytotoxic agent in pretreated patients with progressive locally advanced or metastatic breast cancer and is still active when used as third- or fourth-line treatment.

Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion.

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.

Bio-analysis of docetaxel and hydroxylated metabolites in human plasma by high-performance liquid chromatography and automated solid-phase extraction.

A semi-automated reversed-phase high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of the novel anticancer drug docetaxel in human plasma. The chromatographic system also separated putative hydroxylated metabolites. A limited validation was performed for the assay of the metabolites while these reference compounds were not available in large quantities. The sample pretreatment of the plasma samples involves a solid-phase extraction (SPE) on Cyano end-capped columns. 2'-Methylpaclitaxel was used as internal standard. An APEX-octyl column (150 x 4.6 mm I.D.; particle size 5 microns) was used with acetonitrile-0.02 M ammonium acetate buffer pH 5 mixture as the mobile phase. UV detection was performed at 227 nm. In patient samples hydroxylated docetaxel metabolites were detected and quantified by using the docetaxel calibration curve. The accuracies and precisions of the assay fall within +/- 15% for all quality control samples and within +/- 20% for the lower limit of quantitation, which was 10 ng/ml using 1.00 ml of sample for both the parent drug and its metabolites. The overall recovery of the sample pretreatment procedure for docetaxel was 78.0% +/- 5.8% anc 84.8% +/- 3.1% for the internal standard 2'-methylpaclitaxel. Docetaxel was found to be stable in human plasma at -30 degrees C for at least 6 months. At ambient temperature docetaxel was stable for at most 15 h in human plasma.

Docetaxel alternating with epirubicin and cyclophosphamide: a feasibility study in breast cancer patients.

Docetaxel is one of the most active drugs used in the treatment of breast cancer. However, its major side-effect, myelosuppression, hampers full-dose combination chemotherapy. We have, therefore, developed an alternating schedule of docetaxel with epirubicin and cyclophosphamide, together with granulocyte colony-stimulating factor, to ameliorate neutropenia. We studied the feasibility of such a strategy, decreasing the treatment interval from 21 days to 14 days, thus further increasing the dose intensity. As expected, myelosuppression was common, complicated by neutropenic fever, which did not exceed preset criteria. Other side-effects were also as expected: alopecia, malaise, nausea and vomiting. After two alternating courses of chemotherapy, a partial response was documented in 15 of 17 patients. We conclude that this alternating schedule is very active against breast cancer and warrants further phase II studies.

Treatment of visceral leishmaniasis in a patient with AIDS with antimony and gamma-interferon: remission and prevention of relapse by maintenance therapy with weekly pentamidine.

A 41-year-old AIDS patient with fever, nightly perspiration, diarrhoea, anaemia and leukopenia was diagnosed as having visceral leishmaniasis (VL). After 8 weeks of antimony treatment combined with gamma-interferon, given in 2 courses of 3 and 5 weeks, 12 weeks apart, the bone marrow revealed no parasites by microscopy and culture. Parasitic DNA could still be demonstrated by polymerase chain reaction. Weekly intravenous pentamidine maintenance therapy seemed to prevent relapses. Over time the patient was treated for disseminated M. avium infection, CMV retinitis, porphyria cutanea tarda and renal tubular acidosis. Ultimately he succumbed, 2.5 years after the diagnosis of VL and 4.5 years after the diagnosis of AIDS was established.

Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes.

We analyzed the management of regional lymph nodes in 110 patients with squamous cell carcinoma of the penis treated at the Netherlands Cancer Institute between 1956 and 1989 with curative intent. Of 66 patients who presented with unsuspected nodes 57 were placed on a surveillance program, while lymph node dissection was performed in 5 (with adjuvant external radiation therapy in 1) and 4 were treated with external radiation therapy only. The management of 40 patients with clinically suspected nodes included surveillance in 5, lymph node dissection in 27 (with adjuvant radiotherapy in 11), biopsy in 4 and external radiation therapy in 4. Postoperative radiotherapy had been given if more than 2 nodes were involved or when extracapsular growth was observed. Overall, 25 patients had a regional recurrence, 5 of whom could be cured subsequently. All regional recurrences developed within 2 years after primary treatment. Analysis showed 100% survival in histologically proved node negative patients (stage pN0). The success of lymph node dissection was related to the extent of the metastatic spread and to the number of involved nodes. Patients with 1 positive node and unilateral inguinal involvement showed a statistically significant survival advantage compared to patients with more extensive spread. Considering the indications for node dissection we found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes. However, patients with stage T2 grade 3, stage T3 and operable stage T4 tumors should undergo an immediate inguinal node dissection because of the high probability of clinically occult lymph node invasion (in our material more than 50%). With respect to the extent of the node dissection, we found that the likelihood of spread to the contralateral and/or pelvic regions was related to the number of invaded nodes in the inguinal region. We recommend contralateral node dissection and unilateral pelvic node dissection when 2 or more positive nodes are found in the dissected groin specimen. Primary pelvic node dissection should be performed in patients who present initially with cytologically or biopsy proved positive inguinal nodes.(ABSTRACT TRUNCATED AT 400 WORDS)

Squamous cell carcinoma of the penis. II. Treatment of the primary tumor.

The treatment of the primary tumor in 110 patients with squamous cell carcinoma of the penis seen between 1956 and 1989 was reviewed. Small tumors had generally been treated by penis conserving methods, such as circumcision, local excision and external radiotherapy alone or after circumcision or local excision. Since 1982 we have used the neodymium:YAG laser as a penis conserving method. In 51 patients (46%) penis conserving treatment had been performed and 59 (54%) had undergone some form of amputation. Overall, 16 of 110 patients (15%) had local recurrence. The risk of local recurrence after penis conserving therapy was significantly related to T category, with 10% local recurrences in stage T1 tumors in contrast to 32% and 100% in stages T2 and T3 tumors, respectively. All of the recurrences in patients with stage T1 tumors were strictly local and all were salvaged. In our view penis conserving therapy is a safe procedure in patients with stage T1 tumors and should always be attempted first. Amputation is considered to be overtreatment in these cases. Of 6 recurrences in the conservatively treated stage T2 disease group 4 were strictly local. These were all well or moderately differentiated tumors, not exceeding 3.5 cm. in diameter. We suggest penile conservation for this subgroup of T2 tumors. However, partial amputation is recommended for poorly differentiated stage T2 tumors. Local failure was observed in all stage T3 tumors treated with external radiation. In general, penis conservation in stage T3 tumors should not be attempted with the treatment modalities available to date. Comparing the different methods of penis conservation, used in 49 stages T1 and T2 tumors, no difference in local recurrence rate (18%) was observed among surgery, laser and external beam radiation. In view of the low morbidity, cutting and coagulation properties and minimal tissue changes, use of the neodymium:YAG laser would be our first choice of treatment modality. Penile conservation should be attempted only when frequent and long lasting followup is guaranteed, since local recurrences can appear as late as 8 years after primary treatment.

Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology.

Among 118 patients with squamous cell carcinoma of the penis treated at our cancer institute between 1956 and 1989, we analyzed the accuracy of classification, using the tumor, nodes and metastasis system. We analyzed the role of lymphography, computerized tomography and fine needle aspiration cytology as additional staging procedures. The primary tumor (T category) was classified incorrectly in 26% of the cases. Overstaging was noted in 10% of the cases because of unsuspected infiltration and overstaging was noted in 16%. Overstaging occurred because of edema and infection masking the actual size and giving a misconception of infiltration, and also because of primary presentation as large exophytic tumors with no or minimal histopathological infiltration. When the regional lymph nodes were categorized simply as positive or negative 80% of the tumors were classified correctly and 20% incorrectly (13% were false positive and 7% were false negative). Regional lymph node invasion that escaped clinical examination was not detected by any imaging examination or fine needle aspiration cytology study. Positive findings were found only in patients with clinically suspected nodes. The classification of regional nodes by clinical examination only is hardly improved by additional imaging studies. Clinical decisions with respect to the management of regional lymph nodes should not be based on negative findings of lymphangiography, computerized tomography or fine needle aspiration cytology. In patients with proved metastasis additional imaging may be of some help in the detection of pelvic node invasion and the determination of the extent of involvement. We recommend lymphangiography as the examination of choice.

Intracardiac metastases, report of three cases.

Three patients with intracardiac metastases are described, diagnosed by means of physical examination, electrocardiography (ECG) and echocardiography. Cardiac involvement of the heart by malignant disease is not uncommon, but intracardiac metastases have only occasionally been reported. There are only a few case reports of metastases to the heart that were diagnosed antemortem, because these are rarely clinically significant. Two of the reported patients had clear physical evidence of cardiac involvement. A third case was diagnosed as the result of an abnormal ECG.

Time-resolved immunofluorometric assay of human pancreatic isoamylase in serum, with use of two monoclonal antibodies.

This new method for determining pancreatic isoamylase (EC 3.2.1.1) in serum involves two monoclonal antibodies: one immobilized in a microtitration well (the capture antibody), the other biotinylated. After the sample is incubated with the two antibodies, the captured immunocomplex is quantified by adding streptavidin labeled with a europium chelator and measuring the specific Eu3+ fluorescence in a time-resolved mode. Three assay protocols are proposed, involving incubation times of 90, 45, or 25 min. The assay has low (0.005%) cross-reactivity with the salivary isoenzyme. Analytical performance was satisfactory. Results correlate well with results obtained by measuring total amylase activity or by measuring pancreatic isoamylase activity after immunoinhibition. Unlike numerous current amylase assays, this method measures enzyme mass rather than enzyme activity. Potentially, this is a highly specific assay.

Evaluation of commercially formulated aspartate aminotransferase and alanine aminotransferase activity determinations by the Scandinavian Committee on Enzymes and IFCC methods as modified for use with automated enzyme analysers.

The performance characteristics of the Scandinavian Committee on Enzymes (SCE) methods for the assay of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined using six automated enzyme analysers. The reagent formulation did not include pyridoxal phosphate (PLP). An optimal operating mode was defined for each instrument and precision was assessed in greater detail on four instruments. A points rating system was devised to place the instruments in the following order of proficiency: IL Multistat III, LKB-8600, Gilford 3500, ABA 100. In contrast to AST, the ALT activity of patient samples was unstable at -20 degrees C over periods as short as seven days. The performance characteristics of the IFCC methods for assay of AST and ALT activities were determined by using three automated enzyme analyzers in order to assess the effect of PLP upon precision and activity of four quality control sera, and to compare the SCE and IFCC methods. Precision of AST assays did not alter on omission of PLP from the IFCC formulation, while that of ALT assays showed slight deterioration. The decrease in activity on omitting PLP was variable with each instrument. A points-rating system was devised to place the methods in the following order of precision: AST: IFCC (-PLP) 118, IFCC 109, SCE 61; ALT: IFCC 125, IFCC (-PLP) 97, SCE 66. The IFCC methods offer better precision, and the overall change on omitting PLP is minimal.

The diagnostic accuracy of three recommended methods for serum aspartate aminotransferase assays in patients suspected of myocardial infarction and hepatobiliary diseases.

Serum aspartate aminotransferase (AST) activity was measured by the methods recommended by the Scandinavian Committee on Enzymes (SCE) and by the International Federation of Clinical Chemistry (IFCC) with pyridoxal phosphate (PLP) and without (-PLP) in one laboratory at 37 degrees C with the Abbott ABA-100 and in another at 30 degrees C with the IL Multistat III. Reference ranges were determined on 195 healthy hospital staff. Sera from 102 patients with suspected hepatobiliary disease (HBD) and 104 with suspected myocardial infarction (MI) were assayed at both laboratories by all three methods. Based on the above reference ranges, all assays with each method at both hospitals were abnormal in 59 of 67 cases with HBD and 53 of 55 with MI. In aggregate, all three methods yielded comparable rates of misclassification (20-23). The SCE method gave highest false negatives (18) and lowest false positives (5); the IFCC method gave lowest false negatives (1) and highest false positives (20); intermediate values of 8 false positives and 12 false negatives were given by the IFCC (-PLP) method. Using receiver operating characteristic (ROC) curves, the SCE method was clearly superior at 30 degrees C, and the IFCC (-PLP) method was marginally superior at 37 degrees C. However, when the decision threshold corresponded with a 2.5% false positive rate in the non-HBD, non-MI patients, the SCE method gave the lowest false negatives at both temperatures and, on the basis of the present data, must be considered to be the method of choice for AST activity determinations.

Improved serum-initiated aspartate aminotransferase assay by inhibition of lactate dehydrogenase with oxamate.

We describe a serum-inititated aspartate aminotransferase (EC 2.6.1.1) assay that obviates the need for added lactate dehydrogenase (EC 1.1.1.27) in the reagent system. Interference from the oxidation of NADH by endogeneous lactate dehydrogenase is eliminated by adding sodium oxamate, a competitive inhibitor of the enzyme. The advantages of oxamate inhibition over lactate dehydrogenase addition are a shorter preincubation period, an increase in the linear range from less than 600 to more than 1400 U/L, no interference from above-normal concentrations of ketoacids, and elimination of bias between serum-initiated and the standard oxoglutarate-initiated assays for aspartate aminotransferase.

Activation of alanine aminotransferase in serum by pyridoxal phosphate.

Alanine aminotransferase activity in serum increases significantly when serum is incubated with pyridoxal phosphate. The increase depends on the L-alanine concentration in the final assay mixture, being greatest at 800 mmol/liter. Preincubation of 22 normal sera, in a 10:1 ratio with an 8.09 mmol/liter pyridoxal phosphate solution, resulted in an increase in the alanine aminotransferase activity from 10.5 +/- 4.9 U/liter (mean +/- SD) to 28.4 +/- 5.3 U/liter, an increase of 170%. The absolute amount of apoalanine aminotransferase is relatively constant over a wide range of enzyme activities.