Jerry L. Klein

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.

Phase I-II studies of yttrium-labeled antiferritin treatment for end-stage Hodgkin's disease, including Radiation Therapy Oncology Group 87-01.

Radiolabeled antiferritin immunoglobulin (Ig) preparations were tested in patients with advanced, end-stage Hodgkins disease. Four patients received indium-111 (111In)-labeled monoclonal antiferritin (QCI). Targeting was not observed in tumor-bearing areas. Instead, scans showed rapid accumulation of QCI in normal liver. Forty-five patients were injected with 111In-labeled polyclonal antiferritin (rabbit, pig, or baboon). Forty (89%) patients showed tumor uptake, with dosimetric estimates ranging from 300 to 3,000 cGy in 1 week for the subsequently administered yttrium-90 (90Y)-labeled antiferritin. Yttrium-labeled antibody caused hematologic toxicity. Treatment-induced toxicity was not observed in any other organ system. Intravenous autologous bone marrow cells, 18 days after the yttrium infusion, accelerated hematopoietic recovery in eight patients receiving 30 mCi or 40 mCi. Hematopoietic recovery after a 20 mCi 90Y-labeled antiferritin infusion was not influenced by an autologous bone marrow transplant. Two patients receiving 20 mCi and one patient receiving 50 mCi remained aplastic after transplantation for unknown reasons. In 29 assessable patients, a 62% response rate was observed; nine of the 18 responses were complete. Responses ranging from 2 to 26 months were more commonly noted in patients with small tumors and long disease histories. Dosimetric calculations did not predict for responses. Recurrences frequently occurred in new areas instead of areas exhibiting bulky disease at the start of the treatment. Complete responses after 90Y antiferritin were significantly (P less than .02) more frequent than in a previous study with iodine-131 (131I) antiferritin. Further improvements are needed to make this new treatment modality curative.

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.

194 Hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: A radiation therapy oncology group study☆

Hepatocellular carcinoma is known to have a doubling time of approximately 41 days. This rapid cell division suggested that hyperfractionated radiation and chemotherapy might add an advantage in gaining remission of this malignancy. One hundred and thirty-five patients (70% with metastasis and/or previous treatment) were prospectively treated with single daily fractions to the liver (3.0 Gy external beam radiation, total dose 21.0 Gy), and chemotherapy for hepatocellular carcinoma. The low dose chemotherapy used in conjunction with the radiation was 2 hr before treatment on days 1, 3, 5, and 7 and consisted of Adriamycin, 15 mg IV and 5-FU, 500 mg IV. These patients were compared to a second group of 59 patients (80% with metastases and/or previous treatment) treated using the same chemotherapy regimen but using hyperfractionated whole liver external beam irradiation (1.2 Gy twice daily, 4 hr between treatments, 5 days per week to 24.0 Gy, 10 MV photons). Response was determined by CT scan tumor volumetric analysis. The response rate for the single daily fraction patient group was 22% and for the new hyperfractionated group, 18% (p = 0.68). Toxicity was evaluated by RTOG criteria. The grade 4 hematologic toxicity noted in the daily fraction patient group was 6%. Among 59 patients treated with the hyperfractionated liver irradiation, 2% experienced grade 4 hematologic toxicity. Esophagitis occurred in 1% of patients in the standard fractionation group and 19% in the hyperfractionated group (p = 0.0001). Grade 1-4 thrombocytopenia occurred in 49% of patients in the conventional group and 68% in the hyperfractionated group (p = 0.03). Normal liver volume changes with treatment were measured with CT scan tumor volumetric analysis. The hyperfractionated group experienced a median of 11 cc increase in liver volume and the conventional group a 46 cc decrease, but the difference was not significant. Hyperfractionated radiation did not demonstrate a significant benefit over standard daily radiation, but acute toxicity appeared to be higher.

Phase I–II study of radiolabeled antibody integrated in the treatment of primary hepatic malignancies

Abstract Primary intrahepatic malignancies have been demonstrated to contain tumor associated antigens which bind radiolabelled anti-CEA and anti-ferritin antibodies. The present study reports the toxicity and possible therapeutic efficacy of radiolabelled antibodies that were administered at 50 and 100 millicurie doses following combination radiation and chemotherapy. Three of 10 patients who entered into the study completed therapy on schedule and have had remissions of 7, 9, and 18 months; 2 of the 3 patients were alive at 1 and 2 years after treatment. Of 5 patients who were administered radioimmunoglobulin, the singular toxicity was 3 weeks of marrow hypoplasia in one patient who susequently recovered. The remaining 5 patients were at various stages of protocol treatment prior to immunoglobulin treatment. Eight of the 10 patients have had computer analysis of sequential computerized axial tomography (CAT) scans obtained during the course of therapy and at follow up examination. No major organ toxicity was noted. Clinical remissions were documented by computer analysis of the CAT scans to determine the percent of residual tumor.

Radiation enhancement of radiolabelled antibody deposition in tumors

Recent clinical observations led to the use of external radiation to increase tumor targeting by radiolabelled 131-I antiferritin. Examination of increased uptake of 131-I labelled antiferritin following external radiation was carried out in syngeneic implanted hepatomas (H4IIE, 3924A, 7800, and 7777). Exposure to 10 Gy increased the tumor: liver uptake ratio from 1.55 to 1.86 for H4IIE; from 1.56 to 2.0 for 7800; from 1.34 to 1.97 for 7777; and from 1.05 to 1.19 for 3924A. The pattern of uptake varied among the different tumor types, reflecting their inherent differences in vascularity, tumor permeability, antigen density and growth rate, all of which influence antibody targeting of the tumors. When tumor and liver were irradiated, the tumor showed increased differential uptake of labelled antibody compared to normal liver. 51-Cr labelled erythrocytes were used to study the relative vascularity and blood pooling in H4IIE hepatoma and normal tissue. External radiation to the tumor did not increase the uptake of 51-Cr labelled erythrocytes in any site. These studies provide an insight into the role of external radiation as a modality that increases radiolabelled antibody targeting in hepatoma.

Dosimetry and treatment planning for 90Y-labelled antiferritin in hepatoma

Radiation absorbed-dose estimates and treatment planning are reported for 11 patients with hepatoma who were administered 90Y-labeled polyclonal antiferritin IgG for therapy in a Phase 1-2 trial. Dosimetric studies included quantitation of the localization and clearance of 111In-labeled antiferritin IgG in tumor and normal tissues and computer-assisted tumor and normal liver volumetrics from X ray CT scans. For the group of patients studied, hepatoma volumes at the time of treatment ranged from 135 to 3442 cm3. Quantitative 111In antiferritin imaging prior to and following 600 or 900 cGy of external-beam irradiation of the primary tumor demonstrated that tumor uptake increased 1.1 to 5.8-fold (mean 2.8) following external beam. In contrast, changes in uptake of radiolabeled antiferritin in normal liver ranged from 0.35 to 2.1-fold (mean 0.93) after external irradiation. Administered activities of 90Y antiferritin ranged from 8 to 37 mCi and were dependent on tumor volume and tumor localization of radiolabeled antiferritin. Following external-beam irradiation, tumor dose rates achieved with 90Y antiferritin ranged from 10 to 20 cGy/hr and normal liver dose rates from 1.1 to 5.7 cGy/h. The corresponding absorbed dose in hepatomas ranged from 900 to 2150 cGy and in normal liver from 80 to 650 cGy. After external-beam irradiation, tumor and normal liver uptake of 90Y antiferritin was consistent with that of 131I antiferritin.

Dosimetry of 131I-labeled anti-ferritin in hepatoma: A model for radioimmunoglobulin dosimetry

Abstract Dosimetric studies are reported for four hepatoma patients treated with 131 I-labeled anti-ferritin following combination radiation and chemotherapy. Administered activities of radiolabeled antibody ranged from 93 to 157 mCi. Studies included liver and tumor volume calculations from sequences of computerized axial tomographic (CAT) scan slices, in-vivo gnantitation of radiolabeled antibody in the liver and tumor, determination of kinetic parameters of radioimmmioglubulin for liver, tumor, and the total body, and computation of dose rates (rad/boor) and dose (rad) for these tissues. Tumor volumes for these patients prior to the administration of radiolabeled antibody ranged from 370 to 920 cm 3 and liver volumes from 900 to 1980 cm 3 . In-vivo quantitation, carried out 4 to 8 days following infusion of 131 I-labeled anti-ferritin, demonstrated tumor-to-liver ratios of about 2:1 for the deposition of radioimmunoglobuBn in these tissues. Mean values of the effective half-life for radiolabeled antibody in the liver and tumor were 7.4 days and for total-body activity 3.6 days, respectively. For the four patients, the calculated 131 I radiation dose for tumor tissue ranged from 1500 to 2200 rad, for liver tissue from 400 to 1000 rad, and for total-body irradiation (TBI) from 110 to 220 rad.

Yttrium 90-labeled antiferritin followed by high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis Hodgkin's disease.

PURPOSE This study was undertaken to examine the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy followed by autologous bone marrow transplantation in patients with poor-prognosis Hodgkins disease. PATIENTS AND METHODS Patients were entered onto this protocol if they had chemotherapy-resistant disease, bulky disease, or extensive prior therapy. Patients received yttrium-labeled antiferritin on day -13, -12, or -11, followed by high-dose cyclophosphamide, carmustine, and etoposide (CBV) on days -6 to -3, and then bone marrow infusion on day 0. RESULTS Twelve patients received both radiolabeled antibody and high-dose chemotherapy followed by autologous transplantation. Two additional patients started the study, but were unable to complete all therapy. Four of 12 patients experienced early transplant-related mortality. Four patients are alive more than 2 years following transplantation and three are free from disease progression at 24+, 25+, and 28+ months following transplantation. The progression-free survival rate at 1 year is estimated to be 21%. Considering the poor prognostic characteristics of these patients, toxicity on this protocol was not necessarily greater than that observed with high-dose chemotherapy alone. CONCLUSION This report demonstrates the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy and autologous bone marrow transplantation.

Polyclonal 90yttrium labeled antiferritin for refractory Hodgkin's disease

Six patients with chemotherapy resistant Hodgkins disease were treated with intravenous polyclonal 90-Yttrium (90Y) labeled antiferritin. Eighteen days after isotope infusion, patients received an autologous bone marrow transplant that was cryopreserved prior to initiation of treatment. Ten (one patient), 20 (four patients), or 30 mCi (two patients) were used. One patient received three cycles, three patients received two cycles, and two patients received one cycle. The same antibody labeled with 111-Indium (111In) was helpful in documenting the absence of anti-antibodies in six out of six patients, the presence of tumor targeting in six out of seven patients, and allowed for dose estimates in two out of six patients. One patient with a complete response received approximately 20 Gy to the tumor, whereas a second patient with 20 Gy to the tumor showed progressive disease. A total of three patients obtained a complete response, one had a partial response, and two patients progressed on treatment. Acute toxicity was limited to bone marrow aplasia, without a clear-cut beneficial effect for transplantation after 20 mCi 90Y and the suggestion of a positive effect after 30 mCi. One patient died in complete remission 26 months after treatment with chronic lung insufficiency, probably unrelated to the isotope treatment. The early observations are that 90Y-labeled antiferritin has a pronounced antitumor effect as a single agent and less normal tissue toxicity than other treatment modalities for Hodgkins disease, such as chemotherapy, external beam radiotherapy, or autologous bone marrow transplantation after high dose chemo/radiotherapy.