Antibody delivery and effector cell activation in a phase II trial of recombinant gamma-interferon and the murine monoclonal antibody CO17-1A in advanced colorectal carcinoma.

Murine monoclonal antibodies of the immunoglobulin G2a isotype interact with human effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) directed against malignant cells which express antigens recognized by these antibodies. gamma-Interferon enhances these effects in vitro. In a Phase I trial of murine monoclonal antibody CO17-1A and recombinant gamma-interferon (rIFN-gamma), we demonstrated that low doses of rIFN-gamma were superior to high doses in augmenting ADCC mediated by treated patients' monocytes. These results formed the basis for a Phase II trial of CO17-1A combined with low dose rIFN-gamma. Nineteen patients with metastatic colorectal carcinoma were treated with four consecutive daily infusions of 1.0 X 10(6) IU/m2 rIFN-gamma, with 150 mg of CO17-1A administered on days 2, 3, and 4. Therapy was tolerated well. Peripheral blood mononuclear cells were purified from patient samples obtained at baseline and at 1, 4, or 24 h following the start of the first rIFN-gamma infusion and were tested for their ability to lyse 111In-labeled cells of the SW1116 colorectal line. Enhancement of monocyte ADCC was seen by 24 h, while lymphocyte ADCC and natural killer activity directed against K562 cells were enhanced to a lesser extent. Nonspecific lysis of SW1116 cells by effectors was not seen at the time points examined. While CO17-1A antigen expression was observed in most biopsies, 131I-labeled CO17-1A imaged positively in less than one-half of the organs known to harbor metastases, and therapeutic antibody delivery was not always demonstrated by immunoperoxidase staining techniques of tissue obtained following therapy. In antigen-positive lesions, tissue pO2 levels appear to identify lesions which would image positively. No objective responses were seen. Our findings suggest that prolonged therapy with low doses of rIFN-gamma potentiates ADCC but that physiological obstacles to therapeutic antibody delivery are significant. In order to evaluate the validity of this therapeutic approach, measures to enhance antibody delivery are needed, starting with systematic evaluations of therapy with escalating doses of CO17-1A combined with low dose rIFN-gamma therapy.

Observations on the predictive value of perfusion lung scans on post-irradiation pulmonary function among 210 patients with bronchogenic carcinoma.

As a component of treatment planning for thoracic irradiation (RT), 210 bronchogenic carcinoma patients seen at the Fox Chase Cancer Center from 1983 to 1990 underwent quantitative perfusion scans, superimposition of their RT treatment fields onto these scans, and pulmonary function testing. These studies were used to prospectively estimate the influence of the planned thoracic irradiation on pulmonary function, as measured by the forced expiratory volume in one second (FEV1). Among the 156 patients with unresected lesions, the mean pre-RT FEV1 was 1.71 +/- 0.67 liters (+/- standard deviation), and the mean percentage of total lung perfusion within the treatment field was 31.0 +/- 12.1%. Mean values for the 54 patients treated post-operatively were 1.79 liters (pre-RT FEV1) and 28.8% (% perfusion within RT field). Using this technique, the prospectively predicted post-RT FEV1 is the product of the pre-RT FEV1 (1% of total lung perfusion within the treatment field). The mean predicted post-treatment FEV1 for the nonoperative patients was 1.15 +/- 0.43 liters and 1.25 +/- 0.41 liters for the postoperative patients. Forty-three nonoperative and 19 postoperative patients had FEV1 determinations following RT, at a mean post-RT interval of 11 months for nonoperative patients and 23 months for post-operative patients. Among nonoperative patients, 53% had no change in post-RT FEV1, 19% improved, while 22% had readings declining toward the predicted value. Only 5% had readings below predicted. Among postoperative patients, 37% had no change or improvement, 37% declined toward the predicted, 10% declined to predicted, and 11% had values worse than predicted. This technique of superimposing RT fields onto lung perfusion scans predicts for a degree of pulmonary impairment which is observed in only a minority of patients (10%) and which is rarely exceeded (6%).

Prospective prediction of post-radiation therapy lung function using quantitative lung scans and pulmonary function testing.

Surgeons have made use of quantitative perfusion lung scanning (QS) and forced expiratory volume in one second (FEV1) to predict a patient's ability to tolerate lung resection. In this study QS and FEV1 were used to predict prospectively pulmonary function following lung irradiation (XRT). Twenty-two patients have had QS and FEV1 determined before XRT and at planned intervals post-XRT. Serial determination of lung function post-XRT allows comment on the temporal nature of the XRT effect on lung function. Seventeen patients had QS and FEV1 determined at an interval of 2-6 months post-irradiation with a drop in the groups mean FEV1 from 1.91 to 1.87L. or 2% during that interval. In the interval from 6-12 months post-XRT, 13 patients had studies with the groups mean FEV1 dropping from 1.79 to 1.58L or 12% of the original. In the interval from 12-18 months, 6 patients had a decline in mean FEV1 from 1.73 to 1.56L. or 10% of the original. In 22 patients a predicted final FEV1 was compared with a measured value at an interval from XRT. Fourteen of these determinations were at intervals greater than 6 months from the start of XRT and 6 at intervals of greater than 1 year. FEV1 was seen to drop during the follow-up intervals toward the predicted value. In only 2 patients did the final FEV1 drop below the predicted FEV1 and never by more than 0.12L. (6%). In summary, a method for predicting post-XRT pulmonary function using QS and FEV1 is described. Serial follow-up revealed a latent period followed by a late phase where FEV1 fell toward, but not significantly below, the predicted value. Such a determination can be of value in formulating a treatment plan for patients with significantly diminished pulmonary function.

Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy.

Oxygen distribution was measured in 31 fixed lymph node metastases (mean diameter 4.4 cm +/- 0.8 cm) from squamous cell carcinoma of the head and neck by passing a needle electrode through each tumor under CT guidance. Thirteen tumors had uniform oxygen distribution with all measurements under 10 mm Hg. Six tumors had uniform oxygen distribution with all measurements above 10 mm Hg, and twelve tumors had variable oxygen distribution with measurements higher in the periphery than in the center. Response to radiation therapy was judged by changes in tumor volume 90 days following completion of therapy compared to pre-therapy volume. Eighteen tumors were considered complete responders (CR); eleven, non-responders (NR); two, partial responders (PR). No statistically significant difference in radiation dose or tumor size was seen in the PR and CR groups. Mean pO2 was 20.6 (+/- 4.4) mm Hg in the CR group and 4.7 (+/- 3.0) mm Hg in the NR group (p less than 0.001). Normalized pO2 content defined as the total tumor oxygen content normalized by dividing by the volume was 37.4 (+/- 8.2) mm Hg in the CR group and 8.2 (+/- 5.1) mm Hg in the NR group (p less than 0.001). The volume and oxygen levels of each tumor were tabulated and analyzed. Twelve tumors had greater than 26% of their volume containing a pO2 less than 8 mm Hg. Eleven of these were NR and one PR. Nineteen tumors had less than 26% of their volume containing a pO2 less than 8 mm Hg. Eighteen were CR and one PR (p less than 0.001). These data suggest that oxygen plays a significant role in human tumor response to radiation therapy. Oxygen measurements appear to allow separation of subgroups of patients with a poor prognosis who would most benefit from maneuvers to circumvent the hypoxic effect.

Comparison of clinical and computed tomographic staging of head and neck tumors.

The extent of tumor was staged independently using conventional clinical methods and high-resolution computed tomography (CT) in 100 patients with tumors at the base of the skull, nasopharynx, oropharynx, hypopharynx, larynx, nose, and paranasal sinuses. Conventional clinical methods used for staging included physical examination, routine biopsy, routine radiography, tomography, and sonography when appropriate. In 10 patients, CT identified tumors that had not been apparent clinically; eight of these were in the nasopharynx and two in the hypopharynx. In another 26 patients, CT showed the tumor to be more locally extensive than had been evident clinically; 12 of these tumors were in the oropharynx. A new technique of CT-guided biopsy of head and neck tumors was used in 20 patients to attain histologic information or to confirm the extent of the tumor. Thus, information obtained by CT scanning or CT-guided biopsy significantly altered treatment planning in 36 of the 100 patients.

CT-guided biopsy for the detection and staging of tumors of the head and neck.

Twenty patients underwent computed tomography (CT)-guided thin-needle biopsy of tumors of the had and neck without complication. This technique was found to have wide application in confirming the presence and extent of primary disease as well as documenting nodal and bony metastases not apparent clinically.

External imaging techniques for quantitation of distribution of I-131 F(ab')2 fragments of monoclonal antibody in humans.

We have employed noninvasive, external counting techniques for quantitation of I-131 F(ab')2 fragment of mouse monoclonal antibody localized in metastatic lesions and surrounding liver tissue in humans. This method utilizes counts from diametrically opposed views of tumor deposits and surrounding normal tissue. Corrections were made for patient attenuation, lesion size, and surrounding tissue activity. The validity of this method was evaluated using a fillable, tissue-equivalent organ-scanning phantom with organs and tumors of selected size. Less than 10% error was found in quantitation of various activities of I-131 in a 4-cm-diam lesion. Tumor activity ranged from 0.001% to 0.018% of administered dose per cm3 of tissue compared with 0.000 12% to 0.0023% per cm3 of liver. In addition, the vascular clearance of total I-131 and protein-bound I-131 was found to follow a two-compartment model with mean half lives of 3.8 and 21.4 h for total I-131 and 3.9 and 24.4 h for protein-bound I-131.

Quantitative lung scans for prediction of post-radiotherapy pulmonary function.

Quantitative perfusion scans were used to predict the proportion of pulmonary function lost by inclusion of lung in radiotherapy fields. Nineteen patients receiving radiotherapy for carcinoma of the lung had pulmonary function evaluated by forced expiratory volume at 1 second (FEV1) prior to and following radiotherapy. FEV1 measurement followed initiation of radiotherapy from two to 18 months (mean: seven months). Prior to radiotherapy quantitative lung scans were performed with Tc-99m macroaggregated albumin. On images acquired by computer, the radiotherapy field was drawn as a region of interest (ROI) and the proportion of count within this ROI relative to total lung count was determined. The total FEV1 was apportioned by the ROI ratio of count excluded from radiation ROI to total count in lungs to predict the FEV1 expected to be remaining after radiotherapy. In only two cases was the measured post-therapy FEV1 less than predicted (and then, by only 2% and 5%, respectively). The data indicate that quantitative perfusion lung scans can be used to predict conservatively the pulmonary function that may be expected to remain post-radiotherapy. Therapy fields may be adjusted in patients with underlying compromised pulmonary function to conserve a pre-selected FEV1.

Multiple loose bodies in rheumatoid arthritis.

Intra-articular loose bodies are usually secondary to osteochondral fractures, osteochondritis dissecans, synovial osteochondromatosis, and degenerative arthritis. The authors report four patients with longstanding rheumatoid arthritis and multiple loose bodies in a variety of joints. All patients have remained active despite their disease, suggesting that the loose body production was secondary to trauma of continued activity superimposed on joints containing pannus and eroded cartilage.

Tumor detection using radiolabeled monoclonal antibodies.

Radioisotope conjugated to monoclonal antibody products has been used for imaging tumors targeted by the antibody. As imaging progresses, new sets of procedural and technical questions arise. In this chapter, we discuss several current problems in imaging tumor with radiolabeled monoclonal antibody. These include (1) methods for selection of specific antibody and, once the particular antibody is selected, which fragment form is to be used; (2) imaging procedures: what are the optimum imaging parameters, such as optimum time for imaging after administration of tracer and considerations regarding background subtraction; and (3) noninvasive quantitative techniques: quantitation of localization of antibody indirectly from quantitative information in the images.

Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function.

Irradiation (RT) field selection for bronchogenic carcinoma is based on such factors as extent of disease, pulmonary function, and the perceived need for elective nodal irradiation (ENI). A technique of superimposing a patient's RT treatment film onto his quantitative perfusion lung scan can predict the fractional volume of perfused lung receiving RT and has been shown to reliably estimate the minimum post-RT pulmonary function as measured by the forced expiratory volume in one second (FEV1). This technique has been applied to 20 patients with nonresected clinically staged T1-4N0M0 lesions to quantify the pulmonary impact of varying degrees of ENI. The five treatment volumes selected were as follows: (1) tumor volume plus a 2-cm margin; (2) volume 1 plus ipsilateral hilum; (3) volume 2 plus mediastinum; (4) volume 3 plus supraclavicular fossae; and (5) volume 4 plus contralateral hilum. The median pre-RT FEV1 was 2.0 l, and the median predicted minimal post-RT FEV1 for each proposed field was field 1, 1.7 l; field 2, 1.5 l; field 3, 1.3 l; field 4, 1.1.; and field 5, 1.0 l. The decline in median predicted FEV1 with each increase in field size ranged from 2% to 12%, with a broad range of declines for each field. Such quantification can aid in decisions regarding ENI for patients with impaired pulmonary function.

Metastatic colon cancer: correlation of oxygen levels with I-131 F(ab')2 uptake.

Tumor oxygen levels were measured with an electrode in 13 patients with colon carcinoma metastases. These measurements were correlated with images obtained with radiolabeled monoclonal antibody 1083-17-1A. Only those tumors or tumor regions with a mean PO2 of 16 mm Hg or greater were successfully imaged. Tumors and tumor regions with a mean PO2 of less than 16 mm Hg were not imaged, even when the presence of antigen was confirmed with biopsy. These data suggest that physiologic factors other than antigen expression may affect antibody uptake.

Computed tomography guided thin needle biopsy of small lytic bone lesions.

Twelve patients with small lytic bone lesions underwent computed tomography (CT) guided thin (22-gauge) needle biopsy when fluoroscopic guidance was not possible. Adequate tissue for diagnosis was obtained in all twelve patients without complications. CT can be invaluable in directing the needle to a small lesion, detecting extraosseous extention of tumor for biopsy, and avoiding overlying bony structures.

Computed-tomographic-guided biopsy of small apical and peripheral upper-lobe lung masses.

After undergoing unsuccessful bronchoscopic and fluoroscopic biopsy attempts, 15 patients with small, peripheral upper-lobe and apical lung masses underwent computed-tomographic-guided biopsy. Malignant tissue was obtained in all cases. No complications resulted.

Esophageal speech: double-contrast evaluation of the pharyngo-esophageal segment.

Alaryngeal voice is usually accompanied by esophageal speech; however, about 40% of laryngectomy patients are unable to achieve adequate esophageal speech and must rely on mechanical devices for communication. A technique was developed for performing double-contrast studies of the hypopharynx, cervical esophagus, and pharyngo-esophageal segment using thick barium and the air normally injected for speech. Simultaneous audio and video recordings obtained during esophageal speech allowed correlation of the quality of speech with the motion of the pharyngo-esophageal segment. In 35 patients with various degrees of fluency in esophageal speech, normal and abnormal function of the pharyngo-esophageal segment was documented. Inadequate esophageal speech can be related to abnormal motion of the pharyngo-esophageal segment.

Oxygen tension in human tumors: in vivo mapping using CT-guided probes.

The role of oxygen in tumor response to therapy has been studied for several decades. We describe a technique that allows in vivo measurement of oxygen in tumors using computed tomography to guide probes. In the evaluation of 16 tumors, oxygen tensions were found to be substantially lower than surrounding tissue and varied nonrandomly. This technique has allowed construction of detailed tumor oxygen level maps.

Metastatic colon carcinoma detected with radiolabeled F(ab')2 monoclonal antibody fragments.

Nine patients with colonic carcinoma were studied with I-131-labeled F(ab')2 fragments of an anti-colorectal carcinoma monoclonal antibody. A total of 69% of colon cancer sites were detected without background subtraction; metastases from a concurrent breast carcinoma in one patient were not seen. Lesions ranged from 1.5 to 8 cm. The mean thyroid uptake of I-131 at 24 hours was 0.25%. Half-lives of I-131 in the blood (protein-bound and total) fit a two-compartment model, with half-lives of 3.5 and 27.6 hours for the protein-bound fraction and 3.6 and 23.8 hours for total I-131. Using quantitative methods, a mean value of 0.0047%/cm3 of the administered dose was localized in the tumor at peak concentration, which occurred approximately 48 hours post-administration. This has implications for therapy planning.

CT-guided laser therapy in resistant human tumors: phase I clinical trials.

Photodynamic therapy was performed on ten tumors in patients who did not respond to initial therapy and for whom no additional conventional therapy was available. A sensitizing agent (hematoporphyrin derivative [HpD]) was injected directly into each tumor under computed tomographic (CT) guidance to deliver high concentrations to the tumor and to minimize systemic toxicity. Three to 6 days after the injection, a clear Teflon sheath catheter was placed into the tumor under CT guidance. The tumor was exposed to red light (630-nm wavelength) through laser fiberoptics inserted in the sheath. The initial investigation confirmed the technical feasibility of CT-guided photodynamic therapy by means of intratumoral HpD injections and laser exposure through fiberoptics inserted in sheath catheters. The toxicity from a single treatment was minor, and the tumor response was encouraging.