Patient-specific dosimetry of indium-111- and yttrium-90-labeled monoclonal antibody CC49.

UNLABELLED: The objective of this work was to develop patient-specific dosimetry for patients with metastatic gastrointestinal tract cancers who received 111In-CC49 IgG for imaging before therapy with 90Y-CC49 IgG. METHODS: Whole-body imaging of 12 patients, who received 111-185 MBq (3-5 mCi) of 111In-CC49, commenced in < 2 hr postinfusion and was continued daily for 4-5 days. SPECT data were acquired at 24 and 72 hr to determine the range of 111In-CC49 activity concentrations in tumors and normal organs. Time-activity curves were generated from the image data and scaled from 111In-CC49 to 90Y-CC49 for dosimetric purposes. Absorbed-dose calculations for 90Y-CC49 included the mean and range in tumor and normal organs. Computed 90Y-CC49 activity concentrations were compared with measurements on 10 needle biopsies of normal liver and four tumor biopsies. RESULTS: In 9 of 10 normal liver samples, the range of computed 90Y-CC49 activity concentrations bracketed measured values. This was also the case for 3 of 4 tumor biopsies. Absorbed-dose calculations for 90Y-CC49 were based on patients' images and activities in tissue samples and, hence, were patient-specific. CONCLUSION: For the radiolabeled antibody preparations used in this study, quantitative imaging of 111In-CC49 provided the data required for 90Y-CC49 dosimetry. The range of activities in patients' SPECT images was determined for a meaningful comparison of measured and computed values. Knowledge of activity distributions in tumors and normal organs was essential for computing mean values and ranges of absorbed dose and provided a more complete description of the absorbed dose from 90Y-CC49 than was possible with planar methods.

Patient-specific dosimetry using quantitative SPECT imaging and three-dimensional discrete Fourier transform convolution.

UNLABELLED: The objective of this study was to develop a three-dimensional discrete Fourier transform (3D-DFT) convolution method to perform the dosimetry for 131I-labeled antibodies in soft tissues. METHODS: Mathematical and physical phantoms were used to compare 3D-DFT with Monte Carlo transport (MCT) calculations based on the EGS4 code. The mathematical and physical phantoms consisted of a sphere and a cylinder, respectively, containing uniform and non-uniform activity distributions. Quantitative SPECT reconstruction was carried out using the circular harmonic transform (CHT) algorithm. RESULTS: The radial dose profile obtained from MCT calculations and the 3D-DFT convolution method for the mathematical phantom were in close agreement. The root mean square error (RMSE) for the two methods was < 0.1%, with a maximum difference < 21%. Results obtained for the physical phantom gave a RMSE < 0.1% and a maximum difference of < 13%; isodose contours were in good agreement. SPECT data for two patients who had undergone 131I radioimmunotherapy (RIT) were used to compare absorbed-dose rates and isodose rate contours with the two methods of calculation. This yielded a RMSE < 0.02% and a maximum difference of < 13%. CONCLUSION: Our results showed that the 3D-DFT convolution method compared well with MCT calculations. The 3D-DFT approach is computationally much more efficient and, hence, the method of choice. This method is patient-specific and applicable to the dosimetry of soft-tissue tumors and normal organs. It can be implemented on personal computers.

Radiolabeled iododeoxyuridine: safety evaluation.

UNLABELLED: The emphasis of radiolabeled iododeoxyuridine (*IUdR) research at our institution to date has been to assess its safety as a potential therapeutic agent. Toward this goal, we have performed preclinical and clinical studies, using various routes of administration, to detect adverse changes in normal tissues in both humans and animals. As IUdR is rapidly dehalogenated by the liver, the intravenous route is unlikely to be successful in therapeutic efforts. We have therefore focused our attention on more "protected" routes: intra-arterial and intravesicular administration. METHODS: Studies were performed in farm pigs after multiple administrations of [125I]IUdR into the aorta, carotid artery and bladder. IUdR and metabolites were measured in venous blood samples at appropriate time intervals after administration, after which histologic examination of tissues was performed. Studies in human have been performed after intra-arterial administration of [123I]IUdR in patients with liver metastases and intravesicular administration in patients with bladder carcinoma, initially using [123I]IUdR and currently using both [123I]IUdR and [125I]IUdR. Blood samples for pharmacokinetics and metabolite analysis and tissue for autoradiography (when feasible) have been obtained. RESULTS: To date, no evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices have been seen in pigs or humans. When instilled in the bladder, there is little leakage of IUdR in the circulation. CONCLUSION: When [125I]IUdR is used as a therapeutic agent, we anticipate little or no effect on normal tissues.

Survival of patients with resistant Hodgkin's disease after polyclonal yttrium 90-labeled antiferritin treatment.

PURPOSE: A follow-up study was initiated of patients with Hodgkin's disease who were treated with yttrium 90-labeled antiferritin. Prescription method, pharmacokinetics, acute and late side effects, and survival were evaluated. METHODS: Patients had measurable disease and failed > or = two multiagent chemotherapy regimens previously (N = 44). All patients received 5-mCi indium 111-labeled antiferritin 2 mg intravenously and were scanned repeatedly by gamma camera. In five patients, polyclonal antiferritin (rabbit, pig, or baboon) failed to target the tumor. Thirty-nine patients were injected intravenously with 10-, 20-, 30-, 40-, or 50-mCi yttrium 90-labeled antiferritin 2 to 5 mg. Patients received between one and five cycles. Some patients were supported with 5 x 10(7) autologous bone marrow cells per kilogram. RESULTS: Yttrium 90-labeled polyclonal antiferritin does not produce immunologic, pharmacologic, or microbiologic complications in vivo. Bone marrow toxicity is the only side effect observed. Overall response rate is 20 of 39, or 51%. Two patients had stable disease. A significant positive correlation is found between blood radioactivity level 1 hour after radioimmunoconjugate administration and subsequent response of Hodgkin's disease. A dosage in millicuries per kilogram provides a higher positive correlation with blood radioactivity levels 1 hour after administration than a dosage in millicuries per square meter of body-surface area or in total millicuries. Fifty percent of patients survive for > or = 6 months. CONCLUSION: The low-dose protein used (2 to 5 mg) indicates that the high response rate is due to radiation and not to immunologic effects of the antibody. High-activity administrations followed by bone marrow transplantation are not required for tumor response. The therapeutic ratio of radiolabeled antiferritin is higher than the therapeutic ratio observed in most phase I studies of chemotherapeutic agents. This analysis does not identify a superior mode of treatment for patients with end-stage Hodgkin's disease. However, in a heavily pretreated patient population, prolonged survival is observed after relatively inexpensive treatment. Preclinical research with yttrium 90-labeled antiferritin indicates that significant increases in tumor dose can be obtained in the future without an increase in normal tissue toxicity.

Induction of high grade astrocytoma (HGA) by protons: molecular mechanisms and RBE considerations.

Protons of a specific energy, 55 MeV, have been found to induce primary high grade astrocytomas (HGA) in the Rhesus monkey (Macaca mulatta). Brain tumors of this type were not induced by protons of other energies (32-2,300 MeV). Induction of HGA has been identified in human patients who have had radiation therapy to the head. We believe that the induction of HGA in the monkey is a consequence of dose distribution, not some unique "toxic" property of protons. Comparison of the human experience with the monkey data indicates the RBE for induction of brain tumors to be about one. It is unlikely that protons cause an unusual change in oncogenic expression, as compared to conventional electromagnetic radiation.

A unified approach to photon and beta particle dosimetry.

UNLABELLED: The purpose of this investigation was to develop a unified and practical method for photon and beta particle dosimetry. METHODS: This was achieved by developing a point-source function that is equally valid for photons and beta particles. This function contains four fitting parameters. These were computed on the basis of Berger's tables for a wide range of photon and beta particle energies. Explicit formulas were derived for the absorbed fraction within and outside of spheres containing a uniform distribution of activity. For photons, calculations of the absorbed fraction at the center of spheres were compared with the results of Monte Carlo calculations. The two methods yielded essentially identical results, validating the approach used in this study. RESULTS: The results of this study show that there are absorbed-dose gradients as a function of distance from the center of a sphere. These should be taken into account in absorbed-dose calculations. For beta particles, it is shown explicitly that for spheres with a radius of 0.08 cm, absorbed-dose rates from 131I and 90Y beta particles are equal. CONCLUSION: An important feature of this work is that calculations can be made on the macroscopic, cellular and subcellular levels. The approach employed and results obtained in this work should be particularly useful for tumor dosimetry in radionuclide therapy and applicable radiobiological investigations.

Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.

Evaluation of indium-111- and yttrium-90-labeled linker-immunoconjugates in nude mice and dogs.

Rapid uptake and slow transit of radioactivity from normal organs are detrimental to any clinical utilized radioimmunoconjugate because they lower the target-to-nontarget ratio and deliver undesirable radiation to normal organs. To mitigate this problem, two labile chemical linkages (EGS and DST) were introduced between a monoclonal antiferritin antibody (QCI) and a chelating agent (DTPA). The biodistribution of labile-linker immunoconjugates (EGS and DST) and stable linker immunoconjugates (DSS and ITCB) were compared. In a nude mouse model, all of the four immunoconjugates labeled with 111In targeted subcutaneously-implanted human tumor cells. Tumor-to-normal organ ratios were enhanced for the EGS linkage in comparison to the two stable linkages. Serial whole-body immunoscintigraphy confirmed the biodistribution study. The EGS and ITCB 90Y-labeled immunoconjugates had biodistributions similar to their respective 111In-labeled immunoconjugates. As the mouse model is not representative of the high uptake of monoclonal antibodies in the human liver, beagle dogs were used to further explore the retention of radiolabel in normal liver. The EGS-linked immunoconjugate significantly reduced the dog liver activity when compared to the ITCB immunoconjugate. The combination of the animal models (mouse and dog) appears to allow for a more compete and optimal preclinical analysis of chelated radiolabeled monoclonal antibodies for diagnosis or treatment and illustrates the potential clinical improvements possible with labile chemical linkages in radioimmunoconjugates.

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 Hodgkin's 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.

An overview of imaging techniques and physical aspects of treatment planning in radioimmunotherapy.

Planar and tomographic imaging techniques and methods of treatment planning in clinical radioimmunotherapy are reviewed. In clinical trials, the data needed for dosimetry and treatment planning are, in most cases, obtained from noninvasive imaging procedures. The required data include tumor and normal organ volumes, the activity of radiolabeled antibodies taken up in these volumes, and the pharmacokinetics of the administered activity of radiolabeled antibodies. Therefore, the topics addressed in this review include: (1) Volume determination of tumors and normal organs from x-ray-computed tomography and magnetic resonance imaging, (2) quantitation of the activity of radiolabeled antibodies in tumors and normal organs from planar gamma camera views, (3) quantitative single-photon emission computed tomography and positron emission tomography, (4) correlative image analysis, and (5) treatment planning in clinical radioimmunotherapy.

Tumor dosimetry in radioimmunotherapy: methods of calculation for beta particles.

Calculational methods of beta-particle dosimetry in radioimmunotherapy (RIT) are reviewed for clinical and experimental studies and computer modeling of tumors. In clinical studies, absorbed-dose estimates are usually based on the in-vivo quantitation of the activity in tumors from gamma camera images. Because of the limited spatial resolution of gamma cameras, clinical dosimetry is necessarily limited to the macroscopic level (macrodosimetry) and the MIRD formalism for absorbed-dose calculations is appropriate. In experimental RIT, tumor dimensions are often comparable to or smaller than the beta-particle range of commonly used radionuclides (for example, 131I, 67Cu, 186Re, 188Re, 90Y) and deviations from the equilibrium dose must be taken into account in absorbed-dose calculations. Additionally, if small tumors are growing rapidly at the time of RIT, the effects of tumor growth will need to be included in absorbed-dose estimates. In computer modeling of absorbed-dose distributions, analytical, numerical, and Monte Carlo methods have been used to investigate the consequences of uniform and nonuniform activity distributions and the effects of inhomogeneous media. Measurements and calculations of the local absorbed dose at the multicellular level have shown that variations in this dose are large. Knowledge of the absorbed dose is essential for any form of radiotherapy. Therefore, it is important that clinical, experimental, and theoretical investigations continue to provide information on tumor dosimetry that is necessary for a better understanding of the radiobiological effects of RIT.

Accuracy of in-vivo assessment of prostatic volume by MRI and transrectal ultrasonography.

More accurate noninvasive estimation of prostate size is important in therapeutic trials for benign prostatic hyperplasia. The accuracy of MRI and transrectal ultrasound (TRUS) in assessing prostate weight was evaluated in 48 patients who underwent radical prostatectomy for stage A or B cancer. The volume derived from the wet weight of the freshly excised specimen was used as a reference. We compared that volume with volume estimates derived from the three-axis linear dimension measurement by MRI and TRUS using a tissue density of 1.05 g/cc and the standard formula for an ellipsoid object. Prostate and seminal vesicle volumes were also computed by contouring T2-weighted 5 mm thick contiguous MR images using a semiautomatic edge detection program and pixel summation. Three-axis volume MRI method versus volume from wet weight has slightly less scatter than TRUS three-axis method (r = 0.85 vs r = 0.81). Contoured MR volume method has the least scatter r = 0.93, statistically better than the linear axis method. Contoured MRI volumetric analysis appears superior to linear MRI or TRUS methods in estimating true prostate volume.

Selection of reagents for human radioimmunotherapy.

Promising response rates are noted in patients with refractory Hodgkin's disease after radioimmunoglobulin therapy (RIT) with Yttrium-90 labeled polyclonal antiferritin. To explore the most efficacious selection of RIT reagents for use in humans, experimental animal data are reviewed for radiolabeled antiferritin and B72.3. Nude mice with subcutaneously implanted human malignancies provide an excellent primary screen for radiolabeled antibodies under consideration for use in humans. They provide information on the potential of a new reagent to target a human malignancy in vivo. The other determinant of the therapeutic ratio of RIT reagents--normal tissue toxicity--is best analyzed in large animals, such as dogs. Hematologic toxicity is dose limiting in all species and best predicted by a prescription of radiolabeled antibodies in mCi per kilogram body weight and the presence or absence of bone marrow targeting. Per cGy, RIT is more effective in causing BM damage in dogs than in rats. In dogs, bone marrow transplantation with autologous cryopreserved bone marrow cells or G-CSF treatment can accelerate hemopoietic recovery and granulopoiesis, respectively, after RIT. When dose escalation beyond bone marrow toxicity is performed, the liver (dog) or the intestinal tract (rat) become the next dose limiting tissue in dose escalation studies. Significant improvement in RIT results will be achieved when the normal liver uptake of chelated monoclonal antibody in dogs and in human patients can be prevented. The described animal models and continued investigations of RIT in patients with endstage Hodgkin's disease will allow for further improvement in the therapeutic ratio of RIT and the applicability of RIT in humans.

Variable low dose rate irradiation (131I-anti-CEA) and integrated low dose chemotherapy in the treatment of nonresectable primary intrahepatic cholangiocarcinoma.

Previous experience using 131I anti-CEA antibody, which irradiates at a variable low dose rate in combination with a multimodality treatment program, has demonstrated acceptable toxicity and response in primary intrahepatic cholangiocarcinoma. In attempting to improve therapy, Cis-platin was added to the prior regimen. Induction therapy was unchanged. One month later, chemotherapy was given (doxorubicin, 15 mg, 5-fluorouracil, 500 mg, plus Cis-platin, 20 mg/M2) followed the next day by outpatient administration of 20 mCi 131I anti-CEA by i.v. bolus. Five days later, 10 mCi was administered. The latter regimen (chemotherapy plus 20 + 10 mCi 131I anti-CEA) was repeated every 2 months using polyclonal antibodies derived from different species (rabbit, pig, baboon, and horse). Twenty-four patients (29% with prior chemotherapy and/or metastases) were prospectively treated according to this regimen. Toxicity was limited to hematologic toxicity and was manifested by thrombocytopenia and leukopenia (17% and 4% grade 4, respectively, according to RTOG toxicity criteria). Tumor remission was evaluated by CT volumetric analysis and demonstrated a 14% response rate for the induction portion of therapy, 24% for the radioimmunoglobulin portion of treatment, and 50% remission rate when all subsequent tumor volumes were compared to the pre-treatment volume (entire program). The median survival for the entire group of patients was 10.1 months. This result is superior to previously reported trials and, in comparison to our previous study (10.1 vs 6.5 months median survival), further advancement in protocol design appears to have been made. In view of the rarity of this disorder, a randomized trial is not possible and strict statistical analyses cannot be made. The mechanism of 131I-anti-CEA variable low dose irradiation and chemotherapy interaction is discussed as well as further potential modifications for treatment improvement.

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 Hodgkin's 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.

Multimodality cisplatin treatment in nonresectable alpha-fetoprotein-positive hepatoma.

Twenty-eight patients with alpha-fetoprotein-positive (AFP+) nonresectable hepatoma have been enrolled in a new multimodality Phase I, II program. Induction therapy consisted of 50 mg/m2 intravenous cisplatin followed by 2100 cGy irradiation to the tumor volume in seven fractions over 10 days. Hepatic arterial infusion of 50 mg/m2 cisplatin (IA-CDDP) was then administered at monthly intervals. Twenty-one patients have completed induction and at least two cycles of IA-CDDP. Twelve-month cumulative survival was 52% for all 28 patients and 69% for the 21 patients completing induction and IA-CDDP. Median survival has not yet been reached. Response rate (complete and partial) was 36% overall and 48% among the 21 patients who completed treatment. The improved survival of the present series of patients as well as the minimal hematologic toxicity suggests possible further integration of new modalities for therapy.

Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01.

The Radiation Therapy Oncology Group (RTOG) conducted a Phase I/II study in hepatocellular cancer that closed on September 9, 1987 and some results presented previously. Here, 17 patient characteristics are evaluated to identify any of prognostic significance. Two hundred sixteen patients were entered and 198 (74% with metastases and/or previous chemotherapy) were evaluable. Treatment began with an induction regimen of external beam radiotherapy to the liver (21.0 Gy, 3.0 Gy/Fx, 10 MV photons, 4 days per week) with low-dose chemotherapy (5-Fluorouracil (FU), 500 mg, i.v.; Doxorubicin, 15 mg, i.v.) on treatment Days 1, 3, 5 and 7. In the later stages of these studies, 56 patients received external beam radiotherapy as hyperfractionated treatment (1.2 Gy twice daily, 4 hours separation, 5 days per week, 24.0 Gy total) with similar chemotherapy. One month following induction therapy, cycles of radiolabeled antibody therapy were given every 2 months. Each cycle was derived from a different species of animal and consisted of 30 mCi I-131 antiferritin, Day 0, and 20 mCi, Day 5. On Day -1, 5-FU, 500 mg, and Adriamycin, 15 mg, were administered. The overall median survival for the entire group, including previously treated patients, was 4.9 months. The median survival for alpha-fetoprotein (AFP) - patients not previously treated was 10.5 months. Median survival for all AFP - patients was 8.5 months and for all AFP + patients was 4.6 months (p = 0.006). Of the 17 pretreatment characteristics investigated for prognostic value Karnofsky Performance Score (KPS) (80-100 vs. less than 80) (p = 0.0001), presence/absence of ascites (p = 0.0002), bilirubin level (less than 1.5 vs. greater than or equal to 1.5) (p = 0.018), SGOT (less than or equal to 35 vs. greater than 35) (p = 0.001); alkaline phosphatase (less than or equal to 95 vs. greater than 95) (p = 0.008) were found to be significant independently using a multivariant regression model. The relative risk of dying for the unfavorable component of each of these characteristics was 2.2, 2.0, 1.5, 1.9 and 1.7, respectively. Good and poor prognostic groups were then defined and compared to a similar patient population (RTOG study 83-19) with confirmation of the validity of the model. When stratification for these overpowering clinical factors was incorporated, AFP status was again significant with a relative death rate 1.80 times higher for AFP+ patients. Our recommendations for structuring future prospective randomized trials are discussed and include stratification by AFP status.

Radiolabeled antibodies: results and potential in cancer therapy.

Radiolabeled antibodies are analyzed from the classical approach in radiation oncology being compared to geometric isotopic implants, external radiation, and tumor-dose response and energy of the isotope used for cytotoxicity. In addition, physiological factors that limit antibody uptake, varied routes of administration, toxicity of treatment, as well as present clinical progress are reviewed.

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.