Hodgkin's disease: new possibilities for clinical research.
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Combined Modality Therapy↗
Biomedical subjects
S E Order
Publications and source records attributed to S E Order.
A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04).
A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity, oropharynx and hypopharynx. From June 1979 to February 1983, 42 patients were randomized with 40 patients available for analysis. In the radiotherapy (RT) only group, 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day, 5 days per week, to a total of 4400 to 5200 rad. In the radiotherapy plus misonidazole group (RT + MISO) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses. The observed side effects associated with misonidazole were: persistent numbness and paresthesia (1 patient), transient peripheral nerve paresis and persistent paresthesia (1 patient), and nausea and vomiting (2 patients). The treatment related morbidities were similar in both groups. Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group. Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue (1 in each group). Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group. The initial complete response rate in the RT group was 53%, versus 48% in the RT + MISO group. The estimated 2-year loco-regional control rates were 10% for RT alone and 17% for RT + MISO (no significancy). These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas. However, high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus, is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers.
Aged↗
Y-90 antiferritin dosimetry in hepatoma.
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Antibodies, Monoclonal↗
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.
Antineoplastic Combined Chemotherapy Protocols↗
Treatment of supratentorial high grade gliomas with split course high fractional dose postoperative radiotherapy.
Ninety-two patients with malignant supratentorial gliomas diagnosed from 1977 to 1983 received split course external beam radiotherapy. The initial course of radiation consisted of 3000 cGy whole brain in ten fractions 5 days a week. After a 2-week rest, treatment was continued to a portal restricted to the computerized tomography scan demonstrated abnormality plus a margin for an additional 2100 cGy (total 5100 cGy/17 fx/36 days). The optic chiasm and hypothalamus were excluded from the high dose region. Following review of all pathologic specimens, three patients with grade II glioma, three lacking histologic confirmation, two unbiopsied and eleven not receiving the prescribed treatment were excluded from the survival analysis. No patients were lost to follow-up. Surviving patients were followed 85 months (median); range 68-125 months. All remaining patients were followed until death. The median actuarial survival for 73 grade III and IV patients was 12.5 months. The 5-year actuarial survival was 10%. The median survival for 54 grade IV patients was 10 months. The 5-year survival was 4%. For 19 grade III patients the median survival was 22.5 months. The 5-year survival was 26%. There was one long-term grade IV survivor (68 mos.) and four long-term grade III survivors (76, 85, 108, 125 mos). No patient developed optic nerve or chiasm injury. One patient, an 85 months survivor, had biopsy documented radionecrosis and hemiparesis. The incidence of necrosis among 62 patients alive 6 months or more (and therefore at risk of brain necrosis) is 1/62 (2%). The incidence among survivors is 1/5. The nominal standard dose for this regimen is 1749 ret. The predictive value of the "nominal standard dose" and "equivalent dose" formulae for brain necrosis is explored. We conclude (a) that this regimen provides a survival probability equivalent to conventional treatment for grade III and IV supratentorial gliomas, (b) that neither the equivalent nor nominal standard doses predicted the incidence of brain necrosis, (c) that the time dose schedule is well tolerated and has an acceptable risk-benefit ratio, (d) that its advantage to the patient is decreased time requirement and cost.
Adolescent↗
Immunoradiotherapy for primary nonresectable hepatocellular carcinoma.
The ability to convert a nonrectable lesion into a resectable one offers significant palliation and possible cure for patients with hepatoma. With increasing effectiveness of radiolabeled immunoglobulin and multimodality treatment, more patients are expected to become candidates for definitive resection after presenting with unresectable disease.
Carcinoma, Hepatocellular↗
Current status of radioimmunoglobulins in the treatment of human malignancy.
Radioimmunoglobulin therapy is a new treatment modality that is easily administered, well tolerated, and can be given on an outpatient basis. It is not, however, as simplistic an approach to cancer therapy as commonly thought. It incorporates the sciences of immunology, physiology, radiobiology, chemistry, and physics, as well as oncology, all of which must be understood if radioimmunoglobulin therapy is to reach its potential. Partial and complete remissions have been achieved while the clinical teams involved in this research are still in the process of defining materials, methods, and future clinical approaches. The authors enumerate the varied problems in the development of radioimmunoglobulin therapy, and report on the current status of clinical trials.
Antibodies, Neoplasm↗
Current status of radioimmunoglobulins in the treatment of human malignancy.
Radioimmunoglobulin therapy is a new treatment modality that is easily administered, well tolerated, and can be given on an outpatient basis. It is not, however, as simplistic an approach to cancer therapy as commonly thought. It incorporates the sciences of immunology, physiology, radiobiology, chemistry, and physics, as well as oncology, all of which must be understood if radioimmunoglobulin therapy is to reach its potential. Partial and complete remissions have been achieved while the clinical teams involved in this research are still in the process of defining materials, methods, and future clinical approaches. The authors enumerate the varied problems in the development of radioimmunoglobulin therapy, and report on the current status of clinical trials.
Antibody Specificity↗
Radiolabeled antibodies in Hodgkin's disease.
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Animals↗
Dosimetry and treatment planning for 90Y-labeled 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.
Antibodies↗
Low-dose-rate total lymphoid irradiation: a new method of rapid immunosuppression.
Total Lymphoid Irradiation (TLI) has been successful in inducing immunosuppression in experimental and clinical applications. However, both the experimental and clinical utility of TLI are hampered by the prolonged treatment courses required (23 days in rats and 30-60 days in humans). Low-dose-rate TLI has the potential of reducing overall treatment time while achieving comparable immunosuppression. This study examines the immunosuppressive activity and treatment toxicity of conventional-dose-rate (23 days) vs low-dose-rate (2-7 days) TLI. Seven groups of Lewis rats were given TLI with 60Co. One group was treated at conventional-dose-rates (80-110 cGy/min) and received 3400 cGy in 17 fractions over 23 days. Six groups were treated at low-dose-rate (7 cGy/min) and received total doses of 800, 1200, 1800, 2400, 3000, and 3400 cGy over 2-7 days. Rats treated at conventional-dose-rates over 23 days and at low-dose-rate over 2-7 days tolerated radiation with minimal toxicity. The level of immunosuppression was tested using allogeneic (Brown-Norway) skin graft survival. Control animals retained allogeneic skin grafts for a mean of 14 days (range 8-21 days). Conventional-dose-rate treated animals (3400 cGy in 23 days) kept their grafts 60 days (range 50-66 days) (p less than .001). Low-dose-rate treated rats (800 to 3400 cGy total dose over 2-7 days) also had prolongation of allogeneic graft survival times following TLI with a dose-response curve established. The graft survival time for the 3400 cGy low-dose-rate group (66 days, range 52-78 days) was not significantly different from the 3400 cGy conventional-dose-rate group (p less than 0.10). When the total dose given was equivalent, low-dose-rate TLI demonstrated an advantage of reduced overall treatment time compared to conventional-dose-rate TLI (7 days vs. 23 days) with no increase in toxicity. This was accomplished without compromise of the immunosuppressant activity of TLI as demonstrated by comparable allogeneic skin graft survival times between the two 3400 cGy treatment groups. This clinical advantage would prove to be beneficial where immediate suppression of the immune system is desirable.
Animals↗
International Clinical Trials in Radiation Oncology. Isotopic immunotherapy: radiolabelled antibody.
The radiolabeled antibody studies of RTOG have introduced a new class of agents in cancer therapy and demonstrated the transport ability of a new technology using agents that cause no acute symptoms, that can be administered in some instances on an out patient basis and that remit active disease in a variety of sites. The potential for new results has been amplified by the recent accomplishment of the chelation of 111-Indium and 90-Yttrium as both dosimetric and therapeutic isotopes linked to antibodies for systemic therapy (Table 2). These developments by a commercial corporation to produce large quantities of radiolabeled antibody agents allow a greater freedom of investigation with these new agents. Once appropriate identification of antibody and dosimetric evaluations are carried out, their additive or singular effects can be studied in a number of malignancies. The need for development of centers to carry out such studies and group-wide dissemination are potential limiting factors. A variety of new combinations of antibody and isotope, increasing specific activity in a number of ways, needs to be investigated in laboratories and in clinics by integrated teams. Radiolabeled antibody therapy has at present the potential to contribute to conventional therapies with both radiation and chemotherapy in a variety of malignancies while not increasing the need for hospitalization and yet minimizing patient discomfort.
Antibodies↗
A comparison of misonidazole sensitized radiation therapy to radiation therapy alone for the palliation of hepatic metastases: results of a Radiation Therapy Oncology Group randomized prospective trial.
Between May 1980 and July 1983, the RTOG conducted a randomized prospective study comparing external radiation therapy and misonidazole to radiation therapy alone for patients with hepatic metastases. Two hundred fourteen patients were accessioned to this study of whom 187 were evaluable. Radiation therapy was delivered to the whole liver to a dose of 21.0 Gy in 7 fractions. Misonidazole was administered orally, 1.5 gm/m2 daily 4-6 hr before each treatment. Patients in the two treatment groups were evenly distributed with respect to stratification variables including primary site, extent of metastatic disease, and Karnofsky Performance Score (KPS). End points examined included amelioration of hepatic pain, improvement of KPS and alkaline phosphatase, decrease in liver and tumor size, and survival. The addition of misonidazole did not significantly improve the therapeutic response to radiation therapy in any of the parameters studied. Hepatic irradiation was effective in relieving abdominal pain with 80% of the symptomatic patients achieving improvement following therapy. Pain was completely relieved in 54% of these patients. Patients with liver metastases from colon carcinoma improved more frequently than those with metastases from other primary tumor sites (p = 0.02). Relief of pain occurred more frequently in patients treated with radiation therapy and misonidazole (87%) compared with radiation therapy alone (74%) (p = 0.08). Palliation of pain was prompt, occurring within a median of 1.7 weeks from the initiation of treatment, and 94% of patients who improved did so within 6 weeks of treatment. The median duration of response was 13.0 weeks in the symptomatic patients; 52% of those surviving 3 months remained improved. KPS improved in 28% of patients. Serial CT scans revealed a partial response in 7% and a marginal response in 13% of patients. One patient had a complete response to treatment. The median survival of patients treated in this series was 4.2 months with no difference between the two treatment groups. Patients with metastases from colon carcinoma and an initial KPS of 80 or more (48% of the patient population) had a median survival of 5.8 months with radiation therapy alone compared with 6.6 months with radiation therapy and misonidazole (p = 0.36). There was no significant treatment related morbidity. Radiation therapy remains an excellent palliative tool for the management of patients with symptomatic hepatic metastases. Further research must continue to identify new methods of selectivity enhancing the tumor response to radiation therapy.
Alkaline Phosphatase↗
Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with 131I anti-CEA--a Radiation Therapy Oncology Group Study.
Thirty-seven patients with primary nonresectable intrahepatic cholangiocarcinoma (57% with prior treatment and/or metastasis) were prospectively treated with external radiation, chemotherapy, and 131I labelled anti-CEA. Therapy began in all trials with whole liver irradiation (21.0 Gy, 3.0 Gy/Fx, 4 days/week, 10 MV photons) with alternate treatment day chemotherapy (Adriamycin, 15 mg + 5-FU, 500 mg). One month after external beam therapy, chemotherapy was given (Adriamycin, 15 mg + 5-FU, 500 mg) followed the next day by the first administration of 131I anti-CEA. The treatment schedule used was 20 mCi day 0; 10 mCi day 5 as an outpatient. This schedule was derived from tumor dose estimates which indicated that 20 mCi (8-10 mCi/mg IgG) was sufficient to achieve tumor saturation with a tumor effective half-life of 3 to 5 days, depending upon the species of animal from which the antibody was obtained. The median tumor dose for the 20 mCi + 10 mCi regimen was 6.2 Gy. Antibody therapy was delivered in 2-month cycles using antibody generated in different species of animals; rabbit, pig, monkey, and bovine. Toxicity was limited to hematologic toxicity and was manifested as thrombocytopenia and leukocytopenia (3.2% Grade IV for each according to RTOG toxicity criteria). Tumor remission evaluated by CT scan digitized tumor volume analysis indicated a 26.6% partial response (PR). Tumor remission by physical examination indicated a 33.3% remission rate (25.9% PR and 7.4% complete remission (CR]. The median survival for patients who responded was 15.2 months. The actuarial median survival for the entire group of patients (metastases and previous treatment) was 6.5 months. The longest partial remission is presently more than 4 years.
Adenoma, Bile Duct↗
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.
Animals↗
Conversion by new treatment modalities of nonresectable to resectable hepatocellular cancer.
Eleven patients with hepatocellular cancer had nonresectable lesions, ten as determined by laparotomy and one by computed tomographic (CT) evidence of inferior vena caval invasion. These patients were treated with a variety of new modalities, particularly radiolabeled antiferritin antibodies. Following treatment, seven of the 11 patients were considered to have converted their lesions to possible resectability. Six patients had complete resections, and one patient was partially resected. All patients had the common features of either nodular massive or nodular multifocal hepatocellular cancer. Relative to the patient's initial status, the quality of life remains high, and a new approach in the treatment of the nodular form of nonresectable hepatoma has been demonstrated. The present rate of such conversion to resectability is unknown. However, with further advances in radiolabeled antibody therapy, these results offer a new opportunity in the management of hepatocellular cancer.
Antibodies, Monoclonal↗
Hepatoma: model for radiolabeled antibody in cancer treatment.
Hepatocellular cancer, due to its size and location, allows tumor volume reconstruction and dosimetric determination when radiolabeled antibodies are administered during therapy. Factors identified in the treatment of this cancer may have general applicability for the radiolabeled antibody treatment of other malignancies. These factors include antibody preparations, labeling levels, and toxic effects. New findings regarding tumor volume saturation and altered tumor vascular permeability following radiation have important implications and should be investigated in other tumor systems. Another important development is the use of a new radiolabel, 90Y, in cyclic therapy, which is the sequential use of antibodies derived from different species. This therapy has increased the radiation dose to the tumor.
Antibodies↗
The correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and disease-free survival. A univariate and multivariate analysis.
A multivariate Cox's hazard function analysis was performed on the prognostic variables selected from 240 patients with localized carcinoma of the prostate who received external beam radiotherapy to analyze the association between the method of biopsy and disease-free survival. The patients received 4500 cGy to the pelvis followed by a 2-week treatment rest and then an additional 2000 cGy to the reduced prostatic volume. Median follow-up was 4 years (range, 1-9 years). The 5-year actuarial local control rate was 91%. There was no difference in local control relative to the method of biopsy (needle biopsy or transurethral resection of the prostate [TURP]). The 5-year actuarial risks of metastases were 28% and 48% for the needle biopsy and TURP groups, respectively (P less than 0.01). The 5-year disease-free survival for the needle biopsy and TURP groups were 55% and 42%, respectively (P less than 0.05). This difference maintained statistical significance for Stage C and Grade III tumors. A multivariate analysis demonstrated that "method of biopsy" was the third most powerful variable after serum acid phosphatase level and modified Broders' grade in predicting disease-free survival. Patients who had TURP had an almost twofold higher relative risk of disease progression than those who had needle biopsy. This study established the correlation of the method of biopsy with a lower probability of disease-free survival over and above the information obtained from the clinical stage, histologic grade, presence or absence of symptoms of obstruction, acid phosphatase level, and lymph node status. The association of TURP with tumor dissemination is discussed with reference to the mechanism of metastasis formation and prevention.
Biopsy, Needle↗