Ege Devries

Long-term Follow-up of Cardiovascular Risk Factors in Patients Given Chemotherapy for Disseminated Nonseminomatous Testicular Cancer

OBJECTIVE To assess cardiovascular risk factors over time in patients who received chemotherapy for disseminated testicular cancer and were apparently cured. DESIGN Cohort study. SETTING Referral center. PATIENTS Fifty-seven consecutive patients (median age, 28 years; range, 16 to 43 years) who received cisplatin-containing chemotherapy between 1978 and 1985. MEASUREMENTS Serum cholesterol and high-density lipoprotein (HDL) levels, body mass index (BMI), blood pressure, kidney function, and hormonal status were monitored during follow-up after chemotherapy (median follow-up, 88 months; range, 56 to 143 months). The BMI and cholesterol values obtained 4 to 6 years after chemotherapy were compared with values from a sample of healthy, age-matched Dutch men; the cholesterol level was also compared with that of 31 patients treated with orchidectomy for stage I disease. RESULTS The mean cholesterol level in patients at the start of chemotherapy was 3.96 +/- 0.98 mmol/L [153 +/- 38 mg/dL], increasing 4 to 6 years later to 6.12 +/- 1.20 mmol/L [237 +/- 46 mg/dL] (P less than 0.001); 49 of 57 patients had an elevated low-density lipoprotein (LDL) cholesterol level (greater than 3.4 mmol/L [130 mg/dL]), with a mean level of 4.47 +/- 1.05 mmol/L [173 +/- 41 mg/dL]. Compared with a sample of healthy Dutch men, the chemotherapy group had an elevated cholesterol level (P less than 0.05). At 4 to 6 years, the mean HDL cholesterol level was 0.76 +/- 0.18 mmol/L [29 +/- 7 mg/dL], which was low compared with that of the healthy Dutch men (P less than 0.05). The mean BMI for all patients was 2.8% higher than expected 4 to 6 years after chemotherapy (P less than 0.01) but was not higher than expected 7 to 10 years after chemotherapy. CONCLUSIONS In addition to other known late side effects of chemotherapy in patients with testicular cancer, hypercholesterolemia and overweight might represent risk factors for cardiovascular disease in such patients, especially in those who are younger.

High performance liquid chromatographic profiling of tryptophan and related indoles in body fluids and tissues of carcinoid patients.

A high performance liquid chromatographic method with quaternary gradient elution and fluorometric detection was developed for profiling of tryptophan (TRP), 5-hydroxytryptophan, serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) in urine, platelet-rich plasma and (tumour) tissue of patients with carcinoid tumours. Prior to injection, urine samples were diluted and filtered. Platelet-rich plasma and tissue homogenates were prepurified by C18 solid phase extraction. Detection limits were approx. 2 pmol. Results of urinary 5-HT and 5-HIAA compared favourably with those of single component analyses. No consistent diurnal variations were found for TRP, 5-HT and 5-HIAA in 12-h urine samples from 15 healthy adults. Abstinence of 5-HT-rich foods reduced urinary levels of 5-HT and 5-HIAA. C18 extraction of indoles from protein-containing matrices was studied in platelet-rich plasma. Although time-consuming and complicated for daily routine use, the present approach offers particular advantages over single component analyses in the study of TRP metabolism in patients with carcinoid tumours.

Local antitumour treatment in carcinoma patients with bispecific-monoclonal-antibody-redirected T cells

In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24–48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24–48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest tha the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48–72 h after treatment.

PHASE-II AND PHARMACOKINETIC STUDY OF LOBAPLATIN IN PATIENTS WITH RELAPSED OVARIAN-CANCER

In phase I studies, lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mg m-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3/4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P < 0.01). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 +/- 0.5, 3.0 +/- 0.6, and 3.2 +/- 1.1 h mgl-1 for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt/TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 +/- 5% and 24 h after infusion 74 +/- 3% of the lobaplatin dose was excreted in the urine. In conclusion, lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.

Fostriecin : A review of the preclinical data

Fostriecin is a novel antitumor antibiotic. In vitro studies showed that fostriecin inhibits DNA topoisomerase II (Topo II) catalytic activity, protein phosphatases involved with cell-cycle control and histone phosphatases. The relative contribution of these mechanisms to the antitumor activity has not been elucidated, but Topo II inhibition seems to be the major mechanism of action at in vitro cytotoxic fostriecin levels. Tumor cell lines with decreased Topo II content showed similar or increased sensitivity to fostriecin, compared to the parent cell lines. The reduced-folate carrier is probably responsible for the cellular uptake of fostriecin. The possible clinical consequences of these in vitro observations are discussed.

Cisplatin and platinum pharmacokinetics during hyperthermic isolated limb perfusion for human tumours of the extremities.

Cisplatin and platinum pharmacokinetics during hyperthermic isolated limb perfusion for human tumours of the extremities

A quantitative reverse transcriptase polymerase chain reaction-based assay to detect carcinoma cells in peripheral blood

The presence of tumour cells in the circulation may predict disease recurrence and metastasis. To improve on existing methods of cytological or immunocytological detection, we have developed a sensitive and quantitative technique for the detection of carcinoma cells in blood, using the reverse transcriptase polymerase chain reaction (RT-PCR) identifying transcripts of the pancarcinoma-associated tumour marker EGP-2 (KSA or 17-1A antigen). The amount of EGP2 mRNA was quantified using an internal recombinant competitor RNA standard with known concentration and which is both reversely transcribed and co-amplified in the same reaction, allowing for a reliable assessment of the initial amount of EGP2 mRNA in the sample. Calibration studies, seeding blood with MCF-7 breast carcinoma cells, showed that the assay can detect ten tumour cells among 1.0 x 10(6) leucocytes. The PCR assay revealed that normal bone marrow expresses low levels of EGP2 mRNA, although immunocytochemistry with the anti-EGP2 MAb MOC31 could not identify any positively stained cell. Analyses using this RT-PCR assay may prove to have applications to the assessment of circulating tumour cells in clinical samples.

RECENT DEVELOPMENTS IN DIAGNOSIS AND TREATMENT OF METASTATIC CARCINOID-TUMORS

In carcinoid patients a tumour of enterochromaffin cell origin is present, which dependent on the site of origin can result in increased serotonin production. Metastasized carcinoids are often diagnosed by measuring 5-hydroxyindoleacetic acid excretion in the urine. This excretion, however, can be influenced by food intake. On the other hand, serotonin measured in blood platelets is unaffected by food intake and, in addition, is found to be more sensitive. Therapy of metastasized carcinoids is directed at tumour reduction or only reduction of symptoms. Tumour reduction can be achieved surgically or by embolization. Combination chemotherapy has a maximum response percentage of about 33%. Over the last few years, both octreotide and interferon alpha have been used in these patients. They rarely result in a reduction of the tumour size (10-20%). Symptom reduction is achievable in most patients with these agents, however. Recently, increasing knowledge obtained concerning the various serotonin receptors and their antagonists is now being used in the treatment of patients with a metastasized carcinoid. In the future it is expected that the different modalities will be combined increasingly.

A PHASE-I STUDY OF IOBAPLATIN (D-19466) ADMINISTERED BY 72H CONTINUOUS INFUSION

A phase I trial with continuous intravenous infusion of lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) for 72 h was performed to determine the maximum tolerated dose (MTD). Each patient received a single dose level, the total dose of lobaplatin ranged from 30 to 60 mg/m2/72 h every 4 weeks. Eleven patients enroled in this study and received a total of 30 courses of lobaplatin (median 2; range 1-6). Thrombo-cytopenia was the dose-limiting toxicity, it reached WHO grade III in three out of six patients at 45 mg/m2/72 h, and WHO grade IV in two out of two patients at 60 mg/m2/72 h. Leucocytopenia was mild, as was nausea and vomiting. Phlebitis at the infusion site was found in three patients. During this trial there were no signs of renal, neuro- or ototoxicity. One patient with ovarian cancer, pretreated with three different platinum complexes, achieved a partial response now lasting for longer than 6 months. In conclusion, thrombocytopenia is the dose-limiting toxicity of lobaplatin administered by 72 h continuous infusion. The recommended phase II dose for this regimen is 45 mg/m2/72 h every 4 weeks.

Phase II study of intensive chemotherapy with autologous bone marrow transplantation in patients in complete remission of disseminated breast cancer

SummaryBackgroundThis trial studied the disease-free survival after high-dose chemotherapy in patients in complete remission of metastatic breast cancer.Patients and methodsThirty women, mean age 42.2 years (range 33–55) with metastatic breast cancer, received high-dose chemotherapy in a phase II study. Patients were eligible if they were ≤ 55 years of age, had achieved complete remission within 6 months of the initiation of chemotherapy, and had a WHO performance scale of 0 or 1. The high-dose regimen consisted of melphalan 180 mg/m2 and mitoxantrone 60 mg/m2 both divided over 3 days. On day 7 bone marrow and/or peripheral stem cells were infused. After bone marrow recovery, external beam radiation was administered to sites of previous metastatic disease in 15 patients.ResultsApart from leuko- and thrombocytopenia, mucositis was the major side effect. One patient died during the bone marrow transplant period due to an aspergillus infection. The median follow-up since highdose chemotherapy is 25 months (range 13 to 56 months). The median disease-free survival since high-dose chemotherapy is 27 months and the disease free survival is still 43% with an overall survival of 53% at 3 years. In two patients tumor relapse occurred only in the brain; in one patient the only relapse sign was a meningeal carcinosis. At the moment 17 patients are disease-free (13+–56+) months after high-dose chemotherapy.ConclusionUntil now this high-dose regimen in selected patients with complete remission after induction chemotherapy for metastatic breast cancer has a promising disease free survival.