Radiolabeled antibody in the treatment of primary and metastatic liver malignancies.
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Animals↗
Biomedical subjects
S E Order
Publications and source records attributed to S E Order.
Definitive radiotherapy following prostatectomy: results and complications.
Thirty-four patients with carcinoma of the prostate treated by prostatectomy received postoperative external beam radiation. Sixteen patients were treated within 4 months of radical prostatectomy (group 1), 12 patients were treated for prostate carcinoma following initial enucleative prostatectomy for benign hypertrophy (group 2) and 6 patients were treated for palpable local recurrence 4 to 10 years following radical prostatectomy (group 3). The indications for postoperative radiotherapy following radical prostatectomy included extracapsular extension, seminal vesicle invasion, peri-prostatic soft tissue involvement, positive margins or palpable local recurrence. Eighty-five percent of the patients received whole pelvic radiation. All patients then had a 2-week treatment rest followed by a reduced portal to the prostate bed to a dose of 6500 cGy. The local control rate after radiotherapy was 100% with a median follow-up of 4 years. The 5-year actuarial survival and disease-free survival rates for all patients were 82 and 72%, respectively. In group 1, the 5-year actuarial survival and disease-free survival rates were 100 and 91%, respectively. In group 2, these rates were 77 and 64%. Three of the six patients in group 3 died within 30 months of radiotherapy. Fourteen patients (41%) had mild to moderate treatment related symptoms including seven patients (21%) with lower extremity or genital edema, five patients (15%) with urinary stress incontinence, two patients (6%) with urethral stricture and three patients (9%) with proctitis. Six of eight patients who were potent prior to radiation retained potency thereafter. No severe complications occurred. We conclude that external beam radiation therapy administered after prostatectomy resulted in an acceptable therapeutic ratio with 100% local regional control, and an acceptable complication rate (41%).
Aged↗
90Yttrium antiferritin--a new therapeutic radiolabeled antibody.
A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepatocellular cancer. The isotope 90Yttrium has the advantage of no significant external radiation to other individuals, that is, outpatient therapy and potentially more therapeutic power with an increase from 0.3 Mev 131I beta radiation to 0.9 Mev 90Yttrium pure beta radiation. Six patients treated in the Phase I study have had modest hematologic toxicity and two have had partial remissions of their primary tumors. One of these patients has had complete remission of a pulmonary metastasis. The use of external radiation (900 rad) to the primary tumor in advance of radiolabeled antibody administration has increased antibody uptake and increased tumor dose rate and total dose. An extensive study of 90Yttrium antiferritin is planned.
Antibodies↗
Detection of specific anti-antibodies in patients treated with radiolabeled antibody.
Over 100 patients have received cyclic treatment with polyclonal 131I labeled anti-ferritin and anti-carcinoembryonic antigen (CEA) antibodies from different animal species (rabbit, pig, cynomolgous monkey, bovine, and baboon). Because survival was prolonged from original cyclic treatment, retreatment with original antibodies (recycling) became a necessary consideration. An assay using autoradiography of Ouchterlony gels, with diffusion of patients' sera against the varied radiolabeled antibodies, was developed to detect anti-antibody precipitin bands. Anti-antibody could be detected with a sensitivity to the 60 ng level. Sera from 35 patients given from 1 to 7 separate cycles (2 injections/week, total antibody 6 mg/cycle) of radiolabeled foreign antibody were studied for the production of anti-antibodies. Anti-antibodies were detected in 11 of 22 primary hepatoma patients studied, 3 of 4 intrahepatic biliary cancer patients, and 0 of 9 Hodgkin's disease patients. In all but two of the patients, the anti-antibodies produced were specific for the species used in the treatment of the patient. Eight patients were reinjected (recycled) with previously used antibodies and the presence or absence of precipitin bands correlated with the ability of these antibodies to deposit in the tumor or to be rapidly degraded. The importance of this assay is its simplicity, sensitivity, and the rapid detection of anti-antibody activity for patients requiring treatment with radiolabeled antibodies.
Antibodies, Anti-Idiotypic↗
Carcinoma of the prostate in the elderly: the therapeutic ratio of definitive radiotherapy.
Withholding or reducing the intensity and aggressiveness of treatment for elderly cancer patients is a widespread tenet lacking substantiation in the literature. To assess the potential value of definitive external beam radiotherapy in the elderly, an analysis of the therapeutic ratio between local regional control and complications was performed in 34 prostatic cancer patients more than 75 years old. Median followup was 5 years (range 2 to 8 years). The 5-year actuarial local regional control rate was 91 per cent. The 5-year actuarial survival rate was 81 per cent and the 5-year survival rate free of disease was 63 per cent. There were no severe complications. Mild to moderate chronic complications occurred in 3 patients (9 per cent). This treatment resulted in an excellent therapeutic ratio, which demonstrates that external beam radiation can be given to elderly patients with acceptable morbidity and gratifying results.
Actuarial Analysis↗
Skeletal metastases from hepatoma: frequency, distribution, and radiographic features.
Over the past 6 years, the authors evaluated 300 patients with hepatoma as part of phase 1 and 2 treatment protocol trials. Analysis of the available clinical data and radiographic studies revealed 22 patients (7.3%) with skeletal metastases demonstrated by radiography, computed tomography (CT), and/or nuclear scintigraphy. The plain film appearance of skeletal metastases from hepatoma was osteolytic in all cases. CT scanning best demonstrated the expansile, destructive nature of these metastases, which were often associated with large, bulky soft-tissue masses. Skeletal metastases from hepatomas demonstrated increased radiotracer uptake on standard bone scans and were gallium avid, similar to the hepatoma itself. In addition, they could be targeted therapeutically with I-131 antiferritin immunoglobulin. The most frequent sites of skeletal metastases were the ribs, spine, femur, pelvis, and humerus. An initial symptom in ten patients was skeletal pain corresponding to the osseous metastases. In five patients, pathologic fractures of the proximal femur or humerus developed and required total hip replacement or open-reduction internal fixation. Patients with long-standing cirrhosis or known hepatocellular carcinoma who also have skeletal symptoms should be evaluated for possible osseous metastases.
Adult↗
Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate.
From 1975 to 1983, 240 patients with carcinoma of the prostate, Stages A2 to C, were treated with whole pelvic radiation followed by a 2-week rest and then a reduced field of radiation. The reduced prostatic field was evaluated for adequacy of tumor coverage by CT scan or ultrasound. The local regional control rate was 94%, with a 5-year actuarial survival for all stages of 72%. Severe complications occurred in 3% of patients and moderate complications in 13%. Two major factors that were identified as contributing to the risk of complications included previous or subsequent surgical intervention. Our technique of external beam radiotherapy resulted in a favorable therapeutic ratio, that is, excellent local-regional control with minimal morbidity.
Aged↗
CT scanning for radiation therapy treatment planning of hepatoma.
One hundred forty-five patients with hepatoma had CT scanning for radiation therapy treatment planning. In order to demonstrate the anatomical distortions that occur with hepatoma and its effect on treatment planning, a control group of 50 colorectal cancer patients with normal livers was analyzed for comparison. The objectives of planning were to deliver as homogeneous a dose to the whole liver as possible and not to treat more than one of two functional kidneys or more than one-half of both functional kidneys. Conventional AP/PA portals were defined by physical examination, intravenous pyelogram, and bowel gas patterns at simulation and were found to be inadequate for the treatment of 76% of patients with hepatoma and 10% of patients with normal livers. Among the control group patients with no hepatoma, only 10% required oblique portals and 6% could not be treated because of left hydronephrosis or a solitary right kidney. Because the distortion of the liver in hepatoma in relationship to the kidneys required portal modification in 76% of hepatoma cases; 39% required oblique planning, 24% AP/PA, 20% PA and left lateral portals, and 17% required 4-field, 3-field or other plans in order to meet the treatment planning objectives. We concluded that all patients receiving radiation therapy to the liver for hepatoma require CT scanning for optimum radiation therapy treatment planning because of the hepatic distortion that occurs in hepatoma and the requirements of renal tolerance.
Carcinoma, Hepatocellular↗
A model system that predicts effective half-life for radiolabeled antibody therapy.
Radiolabeled antibodies to tumor associated proteins localize in both experimental and clinical cancers. In the therapeutic applications of radiolabeled antibody, tumor effective half-life (composite of biological and physical half-lives), along with the concentration of isotope deposited and energies of the isotope used, determine the tumor dose. Antibodies directed against the same antigenic specificity but derived from different species have varied tumor and whole body effective half-lives and as a result, achieve different tumor doses. In vitro testing does not evaluate the in vivo differences in effective half-life that affect tumor dose. We have developed an animal model to evaluate the effective half-life and biodistribution of radiolabeled immunoglobulin (IgG) from diverse species. To determine the relevance of such a model, the effective half-lives and tissue distributions of the different immunoglobulins in the model were compared to those obtained from the clinical program using the same radiolabeled antibody preparations. In both the experimental model and in the clinical trials, radiolabeled immunospecific and normal IgG derived from monkey, rabbit, and porcine sources had the longest effective half-lives, goat and sheep had intermediate effective half-lives, and chicken and turkey had the shortest effective half-lives. Prescreening of bovine and baboon normal IgG predict long half-lives and similar organ distributions. These species have been immunized for clinical use. Bovine IgG has a long clinical half-life and has been added to our other successful antibodies. Baboon IgG is now ready for clinical testing. The value of this model system is that it appears to be an effective in vivo preclinical screen for tumor effective half-life of antibodies and IgG from diverse species, thus guiding potential clinical use.
Animals↗
New frontiers in the treatment of lung cancer.
Surgical resection still is the only significant curative approach in nonsmall cell lung cancer. Recent surgical experience indicates that a modest decrease in the death rate from bronchogenic carcinoma may occur in three general areas: (1) the detection and treatment of radiographically occult squamous cell carcinoma; (2) the combination of adjuvant chemotherapy and surgical excision in selected patients with small cell carcinoma; and (3) surgical resection and postop irradiation of patients with hilar and mediastinal lymph node metastases. At the time of diagnosis, 80 to 85% of the patients present with unresectable lung cancer. These patients may benefit from other modalities of therapy, i.e., radiotherapy, chemotherapy, or immunotherapy. Failures following radiotherapy in unresectable nonsmall cell lung cancer are due to (1) distant metastasis, (2) local region failure, and (3) local and distant failure. To increase the local control, new methods of treatment have been tried, such as hyperfractionation of radiotherapy and the use of 131I antiferritin immunoglobulin. The development of effective systemic chemotherapy is necessary to treat metastatic bronchogenic carcinoma. The response rate to chemotherapeutic agents is substantially lower in nonsmall cell carcinoma than in small cell carcinoma. Investigation is ongoing to assess the effectiveness of new antitumor drugs used alone, in combination with other drugs, or combined with other modalities for the treatment of bronchogenic carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
Molecular missiles and drug delivery.
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Antibodies, Monoclonal↗
Computed tomography assisted volumetric analysis of primary liver tumor as a measure of response to therapy.
Serial computed tomography assisted volumetric analyses were made in 33 patients with hepatoma. Thirteen of 27 patients with tumor volumes less than 2,290 cc had a partial response to experimental therapy. However, only three of these patients also demonstrated a significant change in liver volume. Tumor volume determinations made by the method described are an accurate (+/- 10%) and reproducible way to measure response to therapy. In spite of small changes in total liver volume, there may be concomitantly substantial changes in tumor volume.
Antineoplastic Combined Chemotherapy Protocols↗
Isotopic immunoglobulin: a new systemic therapy for advanced Hodgkin's disease.
Thirty-eight patients with advanced, progressive Hodgkin's disease who had relapsed from or who had not responded to treatment with at least two potentially curative combination chemotherapy regimens were entered into this phase 2 study. All patients received 131I antiferritin antibody administered intravenously (IV) at a dose of 30 mCi on day 0 and 20 mCi on day 5. Antibody was derived from rabbit, pig, and monkey species. Objective partial remission of measurable disease was recorded in 40% of patients. Symptomatic response was recorded in 77% of patients. Toxicity was restricted to bone marrow depression with thrombocytopenia greater than leukopenia. These responses are comparable to other reported phase 2 drugs in this patient population and subsequent trials of antibody free of radioactivity and antibody using a beta emitting isotope are being carried out to expand upon these results.
Adult↗
Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study.
One hundred five patients with hepatoma were treated with iodine 131 antiferritin in three sequential protocols in phase 1-2 trials. Therapy began in all trials with external beam irradiation and chemotherapy. The dosimetric results with 131I antiferritin indicated that 30 mCi (8 to 10 mCi/mg immunoglobulin G [IgG]) was sufficient to saturate the tumor. Tumor-effective half-life of the radioactive antibody was 3 to 5 days and was dependent on the species of animal from which the antibody was derived. This led to a 30 mCi on day 0 and 20 mCi on day 5 treatment schedule. Toxicity was predominantly thrombocytopenia. Due to clinical remission, cyclic therapy was next developed with antibodies from different species of animals. Rabbit, pig, monkey, and bovine antibodies were determined to produce the longest tumor-effective half-life and therefore the highest dose of radiation. Integration of 15 mg doxorubicin and 500 mg 5-fluorouracil (5-FU) with 131I antiferritin was accomplished next. Remission to external beam radiation was evaluated by computed tomography (CT) scan tumor volume computations that indicated that 22% of the patients had a partial remission (PR) from initial presentation to 1 month following external irradiation and chemotherapy. From the time of radioactive antibody administration, 48% of the patients (7% complete response [CR] and 41% PR) achieved remission to 131I antiferritin. Of 79 patients evaluated by CT scan tumor volumetrics 50% of the patients (7% CR and 43% PR) remitted to the entire treatment regimen. Patients not previously treated and without metastasis who were alpha fetoprotein positive (AFP+) had a 5-month median survival compared with AFP- median survival of 10 1/2 months. There were four CRs with one being 3 years and 6 months. The longest PR was 5 years and 8 months. These studies have demonstrated the toxicity and therapeutic activity of 131I antiferritin and the emerging role of radiolabelled antibody in cancer therapy.
Adolescent↗
Distribution of and physiologic factors that affect 131I-antiferritin tumor localization in experimental hepatoma.
Polyclonal 131I rabbit anti-rat ferritin localizes in the H-4-II-E hepatoma model. The effect of tumor size, vascularity, and ferritin content on tumor localization was examined. The extravascular and intravascular quantity and location of 131I non-specific IgG and 131I-antiferritin IgG in tumors were determined by gamma counter analysis of tissue samples and autoradiography. Separate groups of 8-10 tumor bearing rats with 0.6-1 g, 1-3 g, 4-8 g, 8-14 g, and greater than 14 g tumors were injected with 500 microCi (200 micrograms) of 131I non-specific IgG or 131I-antiferritin. Tumor targeting with antiferritin occurred maximally in primary or metastatic lesions less than 1 g in size. Decreased localization occurred with increasing tumor size and no localization took place in tumors greater than 8 g in size. This finding is independent of administered dose because increasing the amount of injected antiferritin from 2- to 10-fold did not increase the antiferritin/normal IgG targeting ratio in any group of tumors greater than 4 g. The quantity and physical characteristics of the tumor vasculature may in part explain selective tumor localization. Tumor vascularity per gram as measured by 51Cr labeled erythrocytes decreased as tumor size increased. Decreased localization was evident in the necrotic portions of large tumors. Autoradiography of tumor sections revealed that most of the 125I-IgG activity is deposited perivascularly with decreased deposition of antibody in necrotic areas of tumors and at increasing distance from the lumen of vessels. These findings have clinical importance since this non-homogeneous distribution of antibody could result in the delivery of low doses of radiation to large necrotic areas of tumors. These results help to demonstrate some of the complex physiologic factors that affect tumor localization and antibody distribution.
Animals↗
Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers.
Results of dosimetric studies are reported for 30 patients with hepatoma and 5 patients with primary hepatic cholangiocarcinoma who received treatment with 131I-labeled polyclonal antibodies. Studies included liver and tumor volume computations from X-ray CT scans, in vivo quantitation of the activity of radiolabeled antibodies in hepatic tumors and normal liver tissue, and effective half-life measurements. Twenty-two patients with hepatoma were administered 131I-labeled polyclonal anti-ferritin. Five hepatoma patients, who were AFP-positive, were administered anti-alpha-fetoprotein (AFP). Three patients with AFP-positive hepatomas received both 131I-labeled anti-ferritin and anti-AFP in a bolus. The five cholangiocarcinoma patients were treated with 131I-labeled anti-carcinoembryonic antigen (CEA). For administered activities of 30 mCi on day 0 and 20 mCi on day 5, mean values of the radiation dose to hepatomas were approximately 1100 rads for anti-ferritin, 350 rads for anti-AFP, and 960 rads for the combination of anti-ferritin and anti-AFP. Polyclonal anti-ferritin has, therefore, become the antibody of choice in the treatment of hepatoma. The radiation dose to cholangiocarcinomas from 131I-labeled anti-CEA and administered activities of 20 mCi on day 0 and 10 mCi on day 5 was approximately 620 rads. Total-body irradiation for these injection schedules ranged from 30 to 50 rads.
Adenoma, Bile Duct↗
Variables affecting the tumor localization of 131I-antiferritin in experimental hepatoma.
Ferritin is both a normal tissue- and tumor-associated protein. The in vivo localization of 131I-radiolabeled antitumor ferritin and normal IgG antibodies in the H-4-II-E rat hepatoma model was investigated in both tumor and normal tissues over a dose range of 0.67 micrograms to 5 mg of normal and antiferritin IgG and at labeling ratios (microCi 131I per micrograms IgG) of 15:1, 5:1, and 1:10. The total dose from nonpenetrating radiation in rads was calculated and demonstrated a maximum of 2.9 times greater dose deposition (rads) of antiferritin than normal IgG in hepatoma without specific increase in binding in normal tissues. The maximum tumor targeting achieved was dependent on the amount of injected IgG and not on the labeling ratio or procedure. The binding in tumor could be inhibited by unlabeled antiferritin but not by unlabeled normal rabbit IgG and demonstrated the requirement of specificity for tumor binding. Normal tissues did not target with antiferritin. Most normal tissues have a capacity to bind normal and antiferritin IgG nonspecifically that is linear in relationship to the amount of injected IgG. The results demonstrate that 131I-antiferritin selectively targets ferritin-secreting hepatoma over normal tissues and that the amount of targeting is dependent on the amount of antiferritin injected. The physiologic reasons for such selective localization is not known, but the term "biologic window" has been used to describe the differential availability of tumor ferritin for binding.
Animals↗