Robert A. Rostock

Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a phase II study

PURPOSE To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

CT scan modification in the treatment of mediastinal Hodgkin's disease

Seventy‐one patients with Hodgkins disease who were initially treated at Johns Hopkins with radiation or radiation‐chemotherapy from 1975–1980 had a five‐year cumulative disease‐free survival of I‐A—100% (12 patients); II‐A—85% (33 patients); II‐B—83% (seven patients); III‐A—75% (ten patients); and III‐B—66% (nine patients). Fifty patients with mediastinal masses at the time of treatment demonstrated no marginal misses, two mediastinal recurrences (96% local control), and three lung disseminations. CT scan data yielded stage and treatment modification in 60% (9/15) of recent patients with mediastinal Hodgkins disease. This demonstrates the need for routine thoracic scans and individual treatment planning in all mediastinal cases. Recommendations for combination treatment in early stage disease are made only for pericardial or extrathoracic chest wall extension based on CT scan findings, our low failure rates, radiation organ tolerances, and available relapse data in the literature, not arbitrary size designations from upright chest radiographs. It can be concluded that patients with mediastinal Hodgkins disease require CT scan analysis to identify unusual patterns of presentations, sites at risk, and to allow for proper application of radiation portals and/or chemotherapeutic management.

A new design of microwave interstitial applicators for hyperthermia with improved treatment volume

New 915 MHz microwave interstitial applicators with improved treatment volume have been developed for clinical hyperthermia. The applicators are made from semi-rigid miniature coaxial cables by removing sections of the outer copper conductor to create multiple nodes while preserving the integrity of the teflon dielectric insulators. The homogeneity of the temperature distribution along the longitudinal axis is optimized by empirically adjusting the spacing of the gaps between sections of the outer conductor along the length of the applicator. In vitro and in vivo testing of the two-node and three-node microwave applicators show that the treatment volume can be improved by 100% over that of a one-node microwave applicator.

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.

Selective tumor localization in experimental hepatoma by radiolabeled antiferritin antibody

The in vivo localization of 131I-radiolabeled antiferritin and normal IgG in the H-4-II-E rat hepatoma model was investigated by serial necropsy. Groups of 14 to 18 animals were injected with 500 microCi (200 micrograms) of normal and antiferritin IgG. The total dose from the nonpenetrating beta radiation was calculated for tumor and normal tissue, and expressed as a targeting ratio of antiferritin to normal IgG for each organ studied. The results demonstrate 2.9 times greater dose deposition in tumors of animals treated with 131I-antiferritin than with 131I-normal IgG. 131I-antiferritin deposited equivalently in primary tumors and metastatic lesions of similar size. The specific binding in tumors could be competitively inhibited by the addition of unlabeled antiferritin but not unlabeled normal IgG. Specific targeting with 131I-antiferritin comparison to 131I-normal IgG did not occur in any normal tissue. There was considerable variation in the dose deposition in different normal tissues.

Thoracic CT scanning for mediastinal Hodgkin's disease: results and therapeutic implications

Thoracic CT scans were performed on 42 newly diagnosed patients with Hodgkins disease. Five of 10 patients with negative chest X ray (CXR) had abnormal thoracic CT scans. Among the remaining 32 patients with mediastinal Hodgkins disease (MHD) on CXR, pericardial (Ep) and chest wall invasion (Ec) were the two most common sites of involvement which were detectable by CT scan alone. All 14 cases with Ep had M/T greater than or equal to 0.30 and 14 of 21 with M/T greater than or equal to 0.30 had Ep. Six cases had extensive Ec. Ep and Ec accounted for 16 of 19 of the changes in treatment portal or philosophy based on CT scan findings. Because of the high risk of cardiac or pulmonary radiation toxicity in Ep or Ec, radiation treatment alone may be inadequate. Treatment of mediastinal Hodgkins disease is reviewed here. The use of CT scans for identification of Ep, Ec, and other abnormalities will allow for more precise treatment, further define the use of conventional radiotherapy, combined modality therapy or whole lung irradiation, and allow more accurate analysis of treatment results.

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.

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.

Ferritin concentration and 131I-antiferritin tumor localization in an experimental hepatoma

Polyclonal 131I-labeled rabbit anti-rat ferritin was shown to specifically localize in the H4IIe rat hepatoma model. Tumor targeting was shown to be maximal in primary tumors or metastatic lesions less than 1 gram. Radiolabeled antiferritin tumor targeting decreased with increasing tumor size. In this study, ferritin levels were measured in H4IIe tumors grown both in vitro and in vivo. In vitro tumor cells synthesized and secreted ferritin into the medium as measured by radioimmunoassay, and confirmed by the incorporation of 14C-leucine into ferritin synthesis. The concentration of ferritin in the tumor cells as measured by radioimmunoassay remained relatively constant over this same time period. In vivo tumor ferritin levels in whole tumor extracts were highest in small tumors (less than 1 gram) and decreased as the tumors became larger. Serum ferritin levels of tumor-bearing animals paralleled the level in the tumors themselves. The elevated serum ferritin levels in animals with small tumors did not inhibit tumor targeting with radiolabeled antiferritin antibody. These findings are a foundation for understanding the selective tumor targeting of tumor associated proteins by radiolabeled antibodies, which includes factors such as tumor size, vascularity, antigen content, and circulating antigen.

New aspects of Hodgkin's disease: Staging for conservative management

A variety of curative primary and salvage therapies exist for the management of Hodgkins disease (HD). Consideration of the toxicity of initial therapy is becoming critical for long-term patient management. The recommendation for the routine use of combined modality therapy or whole lung irradiation has been made for the treatment of Stage IA and IIA bulky mediastinal HD based on the correlation between chest X-ray data and increased failure rates in patients managed initially with radiation alone. Thoracic CT scan data has yielded important information as to the possible cause of failure in those patients managed with radiation alone and recommendations are made to substage mediastinal HD for conservative management and to reevaluate the routine use of combined modality therapy. The management of Stage IIIA disease with radiation and/or chemotherapy, the role of splenic involvement for therapy, and the proposed value of substaging disease into IIIA1 and IIIA2 anatomic subsets is discussed. Finally, biochemical and immunological testing may play a future role for initial management.