Pharmacokinetics of 111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma.

Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111In-labeled chelate complex unattached to antibody. Analysis of the 111In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.

Radioimmunoimaging in malignant melanoma with 111In-labeled monoclonal antibody 96.5.

A radiolabeled monoclonal antibody (96.5) reactive with an Mr 97,000 antigen found on over 80% of melanoma cell lines and tissue extracts was examined for its ability to detect malignant melanoma metastases in vivo. For imaging purposes, it was conjugated with diethyltriaminepentaacetic acid and subsequently labeled with 111In by chelation. Thirty-one patients with metastatic melanoma received single injections of monoclonal antibody 96.5 at concentrations ranging from 0.5 to 20 mg and at specific activities of 111In ranging from 0.125 to 4 mCi/mg. Total-body scans were performed at various time intervals following administration. No serious side effects were observed. Of a total of 100 previously documented metastatic sites, 50 imaged for a specificity of 50%. The number of sites imaged increased significantly as the amount of antibody administered increased relative to the average radiation dose. Considerable background uptake of isotope was observed in blood pool and other organs with gradual acquisition of label in tumor sites by 48 to 72 h. Hence, tumor imaging of melanoma using 111In-labeled monoclonal antibody 96.5 appeared feasible, especially at antibody doses above 2 mg.

A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.

One hundred fifty-eight patients receiving Adriamycin underwent 226 transjugular biopsy procedures. The specimens were evaluated by electron microscopy for evidence of drug-related cardiotoxicity. Ejection fraction determinations using echocardiographic or nuclear techniques at rest were available for 69% and 81% of the patients, respectively. Analysis of the data revealed a correlation between cumulative Adriamycin dose and biopsy grade (p less than 0.02). No similar relationship existed between cumulative Adriamycin dose and ejection fractions obtained at rest or between biopsy grades and ejection fractions. In patients who underwent serial endomyocardial biopsies and serial ejection fraction determinations, the correlation between changes in biopsy grade and ejection fraction was poor. A change in resting ejection fraction detected by either method did not reliably predict a change in biopsy grade. The poor correlation between ejection fractions and biopsy grades could be due in part to the sensitivity and specificity of the Adriamycin-related structural changes in contrast to the wider range of disease processes that can affect myocardial function, and to the fact that structural changes often precede the ejection fraction abnormalities. The greater sensitivity and specificity of the biopsy grade should prove useful in reducing the risks associated with evaluating new anthracyclines and potential myocardial protectors of Adriamycin toxicity.

Improved tumor localization with increasing dose of indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody ZCE-025 in metastatic colorectal cancer.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen (CEA) react with human colorectal cancer cells, and when labeled with a gamma-emitting radioisotope, may help to localize known and occult metastatic disease. We tested ZCE-025 (Hybritech, Inc, San Diego), a high-affinity immune gamma globulin1 (IgG1) MoAb anti-CEA that does not react with normal granulocyte glycoproteins in a phase I/II trial to determine the reagent's toxicity and its maximum efficacy in detecting metastatic colorectal cancer. Increasing doses of unlabeled ZCE-025 were mixed with 1 mg of Indium-111 (111In)-radiolabeled MoAb and administered intravenously (IV) to 34 patients who had metastatic colorectal cancer. Planar nuclear or single photon emission computed tomographic (SPECT) scans were performed 48 to 72 and 120 to 144 hours later. Total dose of MoAb and scanning sensitivity (number of imaged lesions/number of known lesions) were correlated up to 80 mg. At doses of 2.5 to 20 mg, a mean of 22% of the lesions were imaged; at 40 mg, 77% were imaged (P less than .01). Liver metastases were detected as areas of increased activity ("hot") at the 40 mg dose but showed decreased MoAb uptake at lower doses. At the 40 mg dose normal liver parenchymal uptake of the labeled MoAb was lower with respect to blood pool compared with the other doses. At 80 mg, however, sensitivity of detection declined to 21%. One milligram of 111In-labeled ZCE-025 antibody coinfused with 39 mg of unlabeled antibody appeared optimal for detecting metastatic colorectal cancer, particularly in the liver. Although the exact mechanism(s) for this dose effect is currently unknown, a partial "blocking" effect of unlabeled antibody with a change in MoAb biodistribution may be occurring.

Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients.

Well differentiated thyroid carcinoma was diagnosed in 1,127 patients at The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston from 1951 to 1981. Of those 1,127 patients, 101 had documented pulmonary metastasis. A retrospective analysis was conducted, and these patients were followed up until 1983. The primary tumors in these patients were histologically classified as papillary (67%), follicular (22%), or Hurthle cell (11%). The age at diagnosis ranged from 5-87 yr. Lung metastasis was diagnosed by both chest x-ray and positive uptake of 131I in 49 patients. Forty-two patients had positive chest x-ray results and negative 131I scans, and 10 patients had positive 131I scans and negative chest x-ray results. The patients were treated with radioactive iodine (76%), chemotherapy (9%), external radiotherapy (2%), or supportive care only (14%). Sixty-seven patients subsequently died of thyroid carcinoma. Our studies showed the following. 1) Patients who were younger than 40 yr of age at diagnosis had better prognosis (71% survival) compared with those over 40 yr of age (16% survival; P less than 0.01). 2) Uptake of radioactive iodine by lung metastasis is a favorable prognostic factor, especially in patients with negative radiological findings. Patients treated with radioactive iodine have a longer survival than those not treated with radioactive iodine (P less than 0.002). 3) The incidence of pulmonary metastasis is significantly less in patients who are treated by total thyroidectomy than in those treated with less than total thyroidectomy (P less than 0.03). 4) The incidence of pulmonary metastasis is lowest in patients with papillary carcinoma (9%), compared with that in patients with follicular (13%) or Hurthle cell (25%) carcinoma.

The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients.

This study analyzed the impact of prognostic variables of age, sex, histopathological diagnosis, extent of disease at diagnosis, and surgical intervention on well differentiated thyroid carcinoma and how surgical treatment, radioactive iodine, and radiotherapy influence the patients' outcomes. There have been 1599 patients with well differentiated thyroid cancer treated and followed at the University of Texas M.D. Anderson Cancer Center from 1948 to 1989. The median follow-up for all patients was 11.0 yr, with the maximum follow-up being 43 yr and the minimum follow-up being 1 yr. The patients were predominantly female (2.3:1), with papillary (81%) and intrathyroidal carcinomas (42%) at the time of diagnosis. Sixty-six percent of the patients had a total thyroidectomy, 7% received external radiotherapy, and 46% had radioactive iodine as part of the treatment of the original disease; the overall recurrence rate was 23%, and the death rate was 11%. This study showed that treatment with radioactive iodine was the single most powerful prognostic indicator for increased disease-free interval (P less than 0.001) and that its use significantly increased survival as well. No benefit was obtained from treatment with external radiotherapy. Children had the best overall survival, but of the adult patients, females who had intrathyroidal papillary disease treated with total thyroidectomy, who had been given radioactive iodine, and whose disease had been diagnosed between 20-59 yr of age had the best prognosis.

Detection of metastatic adrenal carcinoma using 131I-6-beta-iodomethyl-19-norcholesterol total body scans.

Adrenal and total body scintigraphs with 131I-6-beta-iodomethyl-19-norcholesterol were obtained in 5 patients who had had prior resection of adrenal cortical carcinoma. The results were compared with roentgenographic findings and liver, bone, and total body gallium-67 citrate scintigraphs. Metastatic lesions were detected with radiolabeled cholesterol in 4 of 5 patients, including 3 liver metastases, 2 bone metastases, and 1 lung metastasis. These lesions were also demonstrated by one or more of the other diagnostic modalities. All initial findings were negative in a fifth patient, who developed brain metastases within two months. The 6-methyl-analog of iodocholesterol makes it possible to detect metastatic adrenocortical carcinoma with total body scans. Whether or not this agent is "tumor specific" and will be of significant clinical utility will have to be determined more fully in a larger series of patients.

Impact of therapy for differentiated carcinoma of the thyroid: an analysis of 706 cases.

A retrospective analysis of clinical and pathological data was conducted on 706 patients (514 females and 192 males) treated for differentiated thyroid carcinoma at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston from 1951 to 1975 and followed to 1981. The histological diagnoses were mixed papillary/follicular carcinoma (66.7%), papillary carcinoma (14.6%), follicular carcinoma (15.3%), or Hurthle cell carcinoma (3.4%). Patients diagnosed before the age of 40 yr lived significantly longer than those diagnosed over the age of 40 yr, and females lived longer than males. According to survival analyses and disease-free intervals, the order of increasing aggressiveness of the tumors was papillary, mixed, follicular, and Hurthle cell. Total thyroidectomy was associated with longer disease-free intervals and fewer recurrences. The 136 patients who received ablative 131I after surgery had fewer recurrences than a matched group who did not, but the disease-free interval and survival rate showed no significant difference. Further classification showed that patients with follicular and mixed tumors, and those who underwent total thyroidectomy benefited from 131I. There were 78 deaths attributed to thyroid cancer in the whole group. Approximately two thirds occurred in the first 10 yr after diagnosis. In conclusion, total thyroidectomy is recommended, when feasible, for differentiated thyroid cancer, followed by ablative 131I therapy, at least for follicular and mixed varieties.

Technetium-99m stannous citrate brain-tumor uptake in mice: concise communication.

The pharmacodynamics of technetium-99m stannous citrate were studies in Yale-Swiss mice bearing a sarcoma-like transplantable brain tumor, and the renal kinetics were determined in normal mice. Using a rating system based on tumor uptake and tumor-to-brain, tumor-to-blood, and tumor-to-skin ratios, the data obtained with this compound were compared with similar data obtained previously in the same model with Tc-99m Fe-(ascorbic acid), Tc-99m Fe-(ascorbic acid)-DTPA, Tc-99m Sn-DTPA, [99mTc] pertechnetate, and [99mTc] pertechnetate with perchlorate predose. Technetium-99m stannous citrate does not appear to achieve tumor localization by a mode different from these other Tc-99m-labeled compounds, nor does it show any potential advantage as a scanning agent in the tumor model.

Kinetics of 111In-bleomycin and 111 In-chlorides in mice.

Indium-111 as the chloride and chelated to bleomycin has been reported useful as a tumor-scanning agent. This report of the kinetics of these compounds compared in Yale-Swiss mice bearing a transplantable, in situ brain sarcoma. Indium-111-chloride, pH 1.5, gave a maximum tumor uptake of 18.5% dose per gram tumor, a maximum tumor-to-brain ratio of 17.0, and a maximum tumor-to-blood ratio of 4.4. Its renal blood clearance was a slow 0.0022 ml/min. Indium-111-bleomycin showed a maximum tumor uptake of 3.0% dose per gram tumor, a maximum tumor-to-brain ratio of 13.5, a maximum tumor-to-blood ratio of 6.8, and renal blood clearance of 0.254 ml/min. The labeling of bleomycin with 111In results in a tracer with localizing properties in this tumor model which are quite different from those obtained with 111In as chloride or that labeled to bleomycin would appear to have significant potential as agents for imaging tumors.

Localization of indium-111 leukocytes in noninfected neoplasms.

Indium-111-labeled autologous leukocyte studies in general carry a high sensitivity, specificity, and accuracy for the investigation of infections and abscesses. However, past studies have described sporadic cases in which 111In leukocytes localized in tumors. Our experience using 111In leukocytes for the investigation of fever of unknown origin in cancer patients, however, indicates a relatively high incidence of 111In leukocyte localization in noninfected neoplasms. Out of the 61 patients studied for fever of unknown origin, 21 patients (34%) manifested abnormal localization of 111In leukocytes in neoplasms without clinical evidence of infection. These included patients with abnormal localization in: (a) lymph nodes, (b) soft-tissue tumors, and (c) bone neoplasms. The tumors included both primary and secondary lesions, and hematologic as well as solid tumors. The mechanism of 111In leukocyte localization in tumors is still not completely explained. Interpretations of 111In leukocyte studies in cancer patients with fever should take into consideration the possibility that localization may occur in neoplastic tissue per se and does not always indicate the presence of infection.

Variable patterns of technetium-99m MAA perfusion in the therapeutically embolized liver.

Hepatic perfusion studies using 99mTc macroaggregate albumin (MAA) particles have been utilized to document arterial catheter position and flow distribution in patients who are to undergo hepatic arterial chemotherapy infusion (HAI). We have recently been treating nonresectable hepatic neoplasms with transcatheter hepatic arterial chemoembolization (HAE) followed by HAI. The MAA perfusion studies in these patients show variable patterns. For this reason, we have reviewed our recent experience with 15 patients who underwent 21 HAEs and HAIs. The arteriograms and the MAA perfusion studies were reviewed and correlated. Early (within 4 hr of embolization) perfusion studies revealed flow reversal, or MAA reflux into an undesirable location in 11 cases. Two selected follow-up scans in 24 hr revealed restoration of flow to the embolized lobe, confirming the proper position of the catheter for HAI. Knowledge of both the hepatic arterial anatomy, and of the specific embolization procedure will allow accurate interpretation of the MAA perfusion study. Initial flow reversal, or MAA reflux, should not be interpretated as a malpositioned catheter, but prompt reevaluation after a period of 24 hr to document restoration of antegrade flow is suggested.

Radiation damage to mouse testis cells from [99mTc] pertechnetate.

The radiation dose and the biologic damage to mouse testis from intravenously administered [99mTc] pertechnetate were studied. The dose was measured for penetrating radiations from Tc-99m, using calibrated thermoluminescent dosimeters and calculations from the uptake of the nuclide in the testis, and was found to be 4.9 rada per mCi of Tc-99. The biologic damage was measured by the decrease in the number of sperm heads in the testis, counted both by hemacytometer and by Coulter counter. In preliminary experiments using external gamma radiation from Cs-137, the number of sperm heads reached a minimum 29 days after irradiation. Twenty-nine days after injection of 5.8 mCi of Tc-99m, which gives 28 rads to the testis, the number of sperm hads decreased to 70% of control. The biologic effect corresponds to that seen after 40 rads of gamma radiation from Cs-137. The damage to mouse testis cells from internally administered Tc-99m as measured in an in vivo system appears to be at least as significant as that from external gamma irradiation, if not more so.

Critical evaluation of serum thyroglobulin levels and I-131 scans in post-therapy patients with differentiated thyroid carcinoma: concise communication.

Serum thyroglobulin measurements by radioimmunoassay were performed in the follow-up of 68 patients with differentiated thyroid carcinoma undergoing I-131 total-body scans following surgery and/or I-131 therapy. Of 12 patients with distant metastases demonstrated by I-131 scan, thyroglobulin levels were elevated (greater than 60 ng/ml) in nine (75%); the remaining 25% either ranged between 20 and 60 ng/ml or were below 20 ng/ml in spite of having functional metastases. Of six patients with only regional lymph-node metastases demonstrated by I-131 scan, only one (16%) had an elevated thyroglobulin level, while two fell in the 20-60 ng/ml range and three were below 20 ng/ml. Of the remaining patients with no metastatic disease demonstrable by I-131 scan, three (6%) had elevated thyroglobulin levels. These patients were subsequently found to have metastatic disease by other criteria. These results suggest caution in the use of thyroglobulin levels as a replacement for I-131 scans in the follow-up of differentiated thyroid carcinoma. Based on our study, however, the two methods complement each other to achieve maximum sensitivity and reliability.

Arterial perfusion with Tc-99m macroaggregated albumin (MAAAP) in monitoring intra-arterial chemotherapy of sarcomas.

Thirty infusion studies with Tc-99m-labeled macroaggregated albumin were carried out in 21 patients who had histologically proven peripheral tumors. Three patterns of tumor perfusion were noted: increased central radioactivity in 13 patients, decreased central radioactivity with or without increased peripheral radioactivity in four, and absence of radioactivity in four. In the last category, all four patients had no evidence of tumor neovascularity by contrast angiography. In all 21 patients the intraneoplastic patterns showed very good correlation between contrast angiography and radionuclide angiography. Pulmonary tracer uptake was documented in all 14 patients who had counts performed over the lungs; one had no evidence of tumor neovascularity by either angiographic study, and only 8 of the 13 remaining (61%) showed evidence of appreciable tumor arteriovenous shunting by contrast angiography. Decreased tumor perfusion, presumably due to vessel spasm, was found in one patient.

Role of nuclear medicine in chemotherapy of malignant lesions.

The major role of nuclear medicine in clinical oncology is in tumor imaging, which includes evaluating specific organs or the entire body for the presence of tumor. Nuclear medicine studies have been used clinically in the initial evaluation of the tumor extent and in the subsequent management of the cancer patient to assess response to treatment, to detect early relapse, and to assist in making decisions concerning follow-up treatment. Technetium-99m macroaggregated albumin perfusion study for intraarterial chemotherapy has been helpful in monitoring the catheter tip, providing a map of regional perfusion at the capillary level (tumor vascularity), evaluating the degree of arteriovenous shunt in tumor bed, and optimizing division of the dose of chemotherapeutic agent when bilateral arterial catheters are used. Quantitative and serial radionuclide angiocardiography has been useful in assessing doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio) toxicity, and 67Ga-citrate imaging has been used to monitor chemotherapy effect on lungs and kidneys. Radionuclide venography can demonstrate suspected thrombus, and the delineation of the vascular anatomy also allows proper placement of another catheter for continuous effective chemotherapy. Serial bone scans have been the primary modality to assess the response of bone metastasis to systemic therapy in breast cancer patients, and nuclear hepatic imaging may show tumor response, hepatocellular dysfunction, and cholecystitis related to chemotherapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental models for evaluation of radioactive tumor-localizing agents.

Although subject to limitations, there is a need for carefully controlled laboratory studies using animal tumor models in research on tumor-localizing agents. This paper reviews the literature relating to the more important transplantable tumor systems, spontaneous or induced, as to origin, host, site, and radioactive agent used. The historical background of animal tumor models is discussed, including such technical aspects as source of tumor, techniques of transplantation, transplantation sites, and maintenance of transplants. Also, considered are the use of animal tumor models as predictive systems, expression of experimental results of quantitative studies of tissue uptake and comparative radionuclide tumor and distributional studies, and suggestions for future studies, such as the need of more intensive study of existing tumor models for a better understanding of the relationship between animal and human tumors, the need for the development of new tumor model systems, and for standardization of experimental protocols and procedures. A total of 48 t,mor models (26 in mice, 11 in rats, 7 in hamsters, 2 in rabbits, and 2 in dogs) are presented in seven tables dividing the models into tumors of epithelial tissue, connective tissue, hematopoietic tissues, melanin-forming tissue, neural tissues, undetermined site of origin or undifferentiated histologic pattern, and miscellaneous background. The use of animal tumor models in cancer research, which utilizes radionuclides, permits the investigator to do many things not permissible with human beings, but the extrapolation of animal results to human beings must be approached with caution, Although malignant disease, whether in animals or man, must be individualized, certain trends in animal studies can be observed. It is the goal of the laboratory investigator to be able to indicate to the clinician those trends or phenomena that, when repeatedly observed in animal model systems, may be applicable to an understanding of malignant disease in man.

Critical evaluation of the gallium-67 scan for surgical patients with lung cancer.

Seventy-five patients with lung cancer underwent a gallium scan and thoracotomy with total mediastinal nodal dissection. Evaluation of mediastinal lymph nodes by means of the gallium scan showed a sensitivity of 23 percent (3/13), a specificity of 82 percent (31/38), an accuracy of 67 percent (34/51), a positive predictive valve of 30 percent (3/10), and a negative predictive value of 76 percent (31/41) in those patients whose primary tumors demonstrated uptake of radioactive gallium. The low sensitivity was due to an inability to detect microscopic disease in mediastinal lymph nodes. The specificity was decreased by gallium-67 uptake in enlarged inflamed nodes that contained no metastases. These results do not support the use of the gallium scan in the selection of patients with lung cancer for thoracotomy.

Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma.

Studies of regional pulmonary function using radioactive 133xenon gas and spirometric tests (forced vital capacity and forced expiratory volume in the first second) were performed before and after unilateral pulmonary resection for cancer of the lung. Ninety-one patients were evaluated; 47 underwent total pneumonectomy, and 44 underwent lobectomy. The postoperative serial evaluations were classified into short-term and long-term studies (less than or more than three months, respectively). The preoperative and postoperative data were utilized to derive formulas for predicting an estimate of the overall functional loss after pulmonary resection based on the number of segments removed. The correlation between the predicted and measured postoperative values was good for resections involving more than three segments (r = 0.83). Prediction for smaller resections was unreliable. While both regional and overall pulmonary functions were relatively stable after pneumonectomy, there was a disproportionate early loss, followed by significant functional improvement with time following lobectomy. The anticipation of and preparation for this early loss of function may be crucial in the treatment of these patients.

Regional and overall pulmonary function changes in lung cancer. Correlations with tumor stage, extent of pulmonary resection, and patient survival.

Spirometry and regional pulmonary function studies using xenon 133 gas were performed in 251 patients who had primary lung cancer. Surgical resection was undertaken in 150 while the remainder were treated with nonsurgical modalities. Pulmonary function studies were repeated postoperatively in 54 patients. Regional ventilation and perfusion of the tumor-bearing lung were decreased in patients with larger primary tumors and in those with involvement of ipsilateral hilar lymph nodes. Reduced regional function was also directly related to the proximity of the primary tumor to the hilum. Significant hypoperfusion did not contraindicate operation in 14 patients; however, 13 of them required pneumonectomy. Estimated postoperative forced expiratory volume in 1 second (FEV1.0), derived from preoperative spirometry and regional function of the tumor-bearing lung, correlated well with the measured postoperative values. These estimations were valuable in determining the extent of safe resection and correlated well with short-term survival. Long-term survival correlated better with the stage of disease.