Thyroid function abnormalities associated with the chronic outpatient administration of recombinant interleukin-2 and recombinant interferon-alpha.

We prospectively examined thyroid function during and following chronic, outpatient therapy with recombinant interleukin-2 (rIL-2) and Roferon-A (rIFN-alpha 2a). Twenty-two of 30 patients with advanced renal cell carcinoma treated on a phase II open pilot study of concomitant rIL-2 and rIFN-alpha 2a were included. Serum levels of thyroxine, triiodothyronine, free thyroxine index, thyrotropin, antithyroid antibodies, and thyrotropin (TSH) receptor binding antibodies were measured before therapy and after every other cycle. Selected patients underwent studies after every cycle and following completion of therapy. Twenty patients (91%) developed laboratory evidence of thyroid dysfunction, 11 (50%) developed hypothyroidism, five (23%) had a biphasic pattern, and four (18%) had hyperthyroidism. The incidence of thyroid dysfunction increased with increased number of treatment cycles. Transient hyperthyroidism was noted in six of the 11 patients studied after the first cycle and persisted after cycle three in only two patients. Hypothyroidism was not observed after cycle 1, but became increasingly frequent between cycles 2 (56%) and 6 (90%). Thyroid function normalized following therapy in nine of 12 patients tested. Antithyroid antibodies were identified pretherapy in five patients (23%) and de novo in none; TSH receptor binding antibodies were not detected. This study demonstrates a remarkably high frequency of reversible thyroid dysfunction in patients with advanced renal cell carcinoma treated with repeated cycles of rIL-2 plus rIFN-alpha 2a. We conclude that chronic therapy with rIL-2 and rIFN-alpha 2a produces thyroid dysfunction in virtually all patients most likely secondary to a nonspecific, nonautoimmune, toxic manifestation of prolonged treatment. IL-2 therapy may, therefore, produce thyroid dysfunction by more than one mechanism.

Clinical use of tumor markers in oncology.

The perfect tumor marker would be one that was produced solely by a tumor and secreted in measurable amounts into body fluids, it should be present only in the presence of cancer, it should identify cancer before it has spread beyond a localized site (i.e., be useful in screening), its quantitative amount in bodily fluids should reflect the bulk of tumor, and the level of the marker should reflect responses to treatment and progressive disease. Unfortunately, no such marker currently exists, although a number of useful but imperfect markers are available. The predominant contemporary markers are discussed here by chemical class, as follows: glycoprotein markers, including carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and prostate specific antigen (PSA); mucinous glycoproteins, including CA 15-3, CA 19-9, mucinous-like cancer antigen and associated antigens, and CA 125; enzymes, including prostatic acid phosphatase (PAP), neuron specific enolase (NSE), lactic acid dehydrogenase (LDH), and placental alkaline phosphatase (PLAP); hormones and related endocrine molecules, including calcitonin, thyroglobulin, and catecholamines; and, molecules of the immune system, including immunoglobulins and beta-2-microglobulin. The biologic properties of each group of tumor markers are discussed, along with our assessment of their role in clinical medicine today.

Alterations in phenotype and cell-surface antigen expression levels of human monocytes: differential response to in vivo administration of rhM-CSF or rhGM-CSF.

We investigated, via multicolor flow cytometry, the in vivo effects of colony-stimulating factors (CSFs) on cell size, frequencies, and expression of surface antigens on peripheral blood monocytes from melanoma patients treated concurrently with CSFs and tumor-specific monoclonal antibody (mAb) R24. Recombinant human macrophage colony-stimulating factor (rhM-CSF) increased cell size, relative percentages of monocytes, percentages of CD14+, HLA-DQ+, CD11b+, and CD16+ monocytes, and cell-surface expressions of HLA-DR and CD11b; rhM-CSF also up-regulated cell-surface expression of CD14 on CD14brightCD16- monocytes. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) increased cell size, percentages of CD14+, HLA-DQ+, and CD11b+ monocytes, and cell-surface expressions of HLA-DR, HLA-DQ, CD11b, and CD58. Relative percentages of monocytes and CD16+ cells and cell-surface expression of CD14 on CD14brightCD16- monocytes decreased. In addition, monocytes derived from patients treated with rhM-CSF showed functional activity when assayed in vitro for antibody-dependent cellular cytotoxicity (ADCC). During treatment and coincident with increased CD16 expression, monocytes derived from rhM-CSF patients had enhanced levels of cytotoxicity towards melanoma target cells compared to healthy controls and to patients treated with rhGM-CSF.

Evaluation of cisplatin, carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase II study of the Southwest Oncology Group.

BACKGROUND: The combined use of cisplatin and carboplatin chemotherapy offers a unique means of platinum dose intensification. Response rates using either of these agents in combination with etoposide are comparable. In a Phase II trial, the authors investigated the combination of cisplatin and carboplatin with etoposide for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Eligible patients were chemotherapy naive and had histologically confirmed, evaluable, or measurable selected Stage IIIB and Stage IV nonsmall cell lung carcinoma. Based upon the results of an earlier Phase I and II pilot study, patients received carboplatin, 225 mg/m2, on Day 1; cisplatin, 50 mg/m2, on Days 2 and 3; and etoposide, 75 mg/m2, on Days 1, 2, and 3 every-4-weeks. RESULTS: Eighty-three patients (75 eligible patients) received chemotherapy with cisplatin, carboplatin, and etoposide. Two patients refused therapy after registration and were not analyzable. Thirty-six of the remaining 75 patients had Grade 4 toxicities, mostly hematologic, and 6 patients died of toxicity. The confirmed response rate was 24% (95% confidence interval, 15-35%). Median progression-free survival was 4 months and the median survival was 8 months. CONCLUSIONS: Combination cisplatin, carboplatin, and etoposide chemotherapy appears to be no better than cisplatin/etoposide or carboplatin/etoposide for the treatment of patients with nonsmall cell lung carcinoma. The toxicity of this regimen may be higher, and therefore it cannot be recommended for general use.

Quantification of glucose utilization in liver metastases: parametric imaging of FDG uptake with PET.

Positron emission tomography (PET) fluorodeoxyglucose (FDG) studies are useful for identifying foci of increased FDG uptake in liver metastases, because of the high glycolytic rate of malignancies, as well as for monitoring changes in tumor glucose metabolism during treatment. We performed 15 kinetic PET FDG studies in four patients with metastatic liver disease. We produced parametric images of glucose metabolism in terms of the rate constant K (ml/min/g) for net phosphorylation of FDG. Tumor K values, estimated with nonlinear regression, correlated well with K values estimated with Patlak graphical analysis (r = 0.96), validating the assumption of low k4* values in liver metastases and supporting the use of pixel by pixel Patlak plot analysis of the data to generate parametric images. In normal liver, high levels of glucose-6-phosphatase produce much higher values of k4* than in liver metastases. Uncorrected Patlak graphical analysis underestimates K in normal liver, but this further increases the contrast between tumor and liver and facilitates both tumor detection and quantification. The technique is computationally feasible and is well suited for serial evaluations of tumor metabolism during treatment.