Measurement of thymidine replacement in patients with high grade gliomas, head and neck tumors, and high grade sarcomas after continuous intravenous infusions of 5-iododeoxyuridine.

Based upon the radiation sensitization properties of the halogenated pyrimidines, 5-iododeoxyuridine (IdUrd) and 5-bromodeoxyuridine, long term i.v. infusions of halogenated pyrimidines in conjunction with fractionated radiation therapy have been evaluated in the treatment of a variety of human malignancies. While clinical studies have attempted to measure the halogenated pyrimidine incorporation, few have successfully related tumor response to the incorporation of IdUrd by the tumor. The present study reports the continuous IdUrd labeling index (number of cells labeled) and the IdUrd corrected replacement (percentage of thymidine replacement in the labeled cells of the population) from the tumors of 17 patients who received continuous infusions of IdUrd (1000 mg/m2/24 h). The tumors treated included four high grade gliomas, five head and neck tumors, four high grade sarcomas, and five other tumors of varying types. Less than 25% of the cells in three of four gliomas incorporated IdUrd after 5-7-day IdUrd infusion time. Corrected replacement for the gliomas ranged from 0 to 4%. In contrast, 63-85% of the cells in the head and neck biopsies were labeled with IdUrd after 3-7-day IdUrd infusions suggesting that these large tumors (3-12 cm diameter) have a high fraction of dividing cells. Corrected replacements values for the head and neck tumor patients ranged from 2.9 to 26.3%. The high grade sarcomas also demonstrated a high percentage of IdUrd labeled cells (57-79%) with three patients having corrected replacements of 7.5-14.2%. The continuous labeling and thymidine replacement data for four patients from whom serial biopsies were taken during IdUrd infusion demonstrated both an increasing IdUrd replacement and continuous labeling index with an increasing duration of IdUrd infusion. The clinical response of both the high grade glioma and head and neck tumor patients indicate that the IdUrd replacement and labeling data may provide some important predictive information with regard to the successful use of the halogenated pyrimidines in clinical radiation trials.

Long-term follow-up on National Cancer Institute Phase I/II study of glioblastoma multiforme treated with iododeoxyuridine and hyperfractionated irradiation.

PURPOSE: We report the results of the final phase I/II program in glioblastoma (GBM) multiforme patients using only hyperfractionated irradiation and intravenous iododeoxyuridine (IdUrd). METHODS: For a decade we investigated halogenated pyrimidine radiosensitizers in an effort to exploit the potential for differential uptake of thymidine analogs between proliferating tumor and normal brain tissues. Trials began with bromodeoxyuridine (BrdUrd) but were changed to IdUrd when the latter proved less photosensitizing. A series of dose-escalating pilot trials led to treatment at a maximum-tolerated dose (MTD) of IdUrd of 1,000 mg/m2/d for two separate 14-day courses, one during the initial radiation field and one during the cone down. The radiotherapy also evolved over time and was hyperfractionated in all cases reported. Over 5 years we accrued 45 patients into the final hyperfractionated, 1,000 mg/m2/d scheme. We report here results on only the patients with minimum follow-up of 1 year (90% had at least 2 years of follow-up) or until death. RESULTS: The results do not indicate a significant benefit for use of sensitizers, as compared with other contemporary and aggressive types of radiation treatment. The median survival has been 11 months, with a 2-year actuarial survival of 9%. As yet, there are no survivors at 3 years. Tumor biopsies at craniotomy showed relatively low sensitizer incorporation. CONCLUSION: The failure of radiosensitizers combined with radiation therapy to show major benefit may be due to patient selection but appears also to be related to the combined problems of poor drug penetration/uptake into tumor, tumor-cell heterogeneity, and a high inherent cellular radioresistance of GBM.

A simple CT aperture emulator for use with a radiotherapy simulator.

Tumor localization in radiation treatment planning often involves the generation of quantitative anatomical data from multiple imaging modalities. It is desirable to take all of the images in the selected treatment position, which is usually decided upon during the initial simulator session. The different scanning modalities are often operated by different staff, at different times and in different locations; thus, it is difficult to ensure consistency in the position of the patient's body, and its documentation, at various times and places. Also, devices such as CT and MR scanners frequently pose restrictions due to their limited apertures. Failure to consider the physical limitations of such scanning equipment at the time of simulation or localization may result in placing the patient in a treatment position which will not fit through the aperture of the CT (or MRI) scanner, or which will result in a clinically important portion of the anatomy being "cut off" in the resulting scans. This can lead to re-simulation of the patient or result in a lack of accurate coordination of simulator and CT scan data. To minimize problems such as these, we have developed a CT Aperture Emulator which can be used at the time of the initial simulation. This is a lightweight "halo" easily attached to the simulator, which mimics the size and shape of the CT aperture. It permits reproducible adjustment of the patient's position, while allowing technologists and physicians to set up the patient with respect to potential CT constraints, in particular with regard to the use of immobilization and support devices. The emulator device also facilitates reproducing a patient's treatment position on the CT scanner. The concept has been found to have additional clinical uses and can be extended to a variety of imaging equipment.

National Cancer Institute (phase II) study of high-grade glioma treated with accelerated hyperfractionated radiation and iododeoxyuridine: results in anaplastic astrocytoma.

PURPOSE: We report the outcome of a Phase II study of a cohort of patients with high-grade glioma treated with accelerated hyperfractionated radiation and the radiation sensitizer, iododeoxyuridine (IdUrd). METHODS AND MATERIALS: Between January 1988 and December 1990, 39 consecutive patients with high-grade glioma were enrolled and treated on a Phase II protocol including hyperfractionated radiation and IdUrd. Thirty-two patients were male and seven were female. Age range was 19 to 71 years with a median age of 38 years. IdUrd (1000 mg/m2 per day) was administered in two separate 14-day courses, the first during the initial radiation field and the second during the final cone-down field. All patients were treated consistently with partial brain technique and received 1.5 Gy/fraction twice daily to a mean total dose of 71.25 Gy (range 66-72 Gy excluding one patient who did not complete treatment). The initial field was treated to 45 Gy followed by a cone-down field covering the tumor volume plus a 1-cm margin to the final dose. Patients were assessed for acute and long-term morbidity and followed for outcome. Two patients had biopsies during the course of treatment. Flow cytometry and high performance liquid chromatography was used to evaluate the labeling index and the percent replacement of IdUrd in the biopsy specimen. RESULTS: Thirty-eight of 39 patients completed therapy. One patient died on treatment at 48 Gy and is included in the survival analysis. No patient was lost to follow-up. Twenty-one patients had Grade 3 (anaplastic astrocytoma) tumors and 18 patients had Grade 4 (glioblastoma multiforme). Median survival for the entire cohort was 23 months. For the glioblastoma multiforme patients, median survival was 15 months. The median survival of the anaplastic astrocytoma patients has not yet been reached. In the patients assessed, the range of IdUrd tumor cell incorporation was only 0-2.4%. CONCLUSION: Accelerated hyperfractionated radiation therapy with IdUrd was administered with acceptable acute toxicity. The major acute side effects of mucositis and thrombocytopenia were related to IdUrd infusion and were dose-dependent. There were no unacceptable acute toxicities referable to the radiation as delivered. With a median potential follow-up of 51 months, the actuarial median survival of the glioblastoma multiforme patients is comparable with the best previously published reports. The outcome of patients with anaplastic astrocytoma compares very favorably with even the most aggressive multi-modality approaches in the recent literature with a minimum of acute morbidity.

Fatal hypereosinophilia with chromosome 15q- in a patient with multiple primary and familial neoplasms.

A man with large-cell carcinoma of the lung, cerebral meningioma, occult adenocarcinoma of the prostate, and follicular adenoma of the thyroid developed symptomatic, rapidly progressive hypereosinophilia with abnormalities of eosinophil ultrastructure and bone marrow karyotype (45,X,15q22-). Although the patient's eosinophilia defied strict classification as idiopathic hypereosinophilic syndrome (HES), simple tumor-associated eosinophilia, or eosinophilic leukemia, it appeared to be incited by the lung cancer and quickly acquired malignant independence. The family had an excess of prostate cancer and lymphoproliferative neoplasms.

The strategic management of serious news.

The oncology clinic is a paradigm for a delivery system of serious news. Transfer of this information is a model for the delicacy in health care worker-patient interactions. There is an art as well as a science to accurately presenting devastating facts while mitigating potentially unnecessary emotional damage. Wide variability in clinic style, and the absence of specific attention in core curriculum and texts, argue for further interdisciplinary dialogue and teaching in this facet of medicine.

Survivors of Hodgkin's disease: prevention of sequelae.

Increasing numbers of patients are surviving Hodgkin's disease in their youth, creating an ever larger cohort who need careful attention to long-term preventive medicine in their older years. Vigilance is especially needed for those who received laparotomy, splenectomy, and irradiation for early stage I through stage III disease, the majority of whom are destined to be long-term survivors. With the frequent migration of the young, these patients often fall under the care of a physician other than their original oncologist. The diligent internist, oncologist, emergency room physician, and general practitioner can avoid several simple pitfalls in the long-term care of these young patients now entering middle age.

Familial respiratory tract cancer. Opportunities for research and prevention.

Case studies of two families with lung and other respiratory tract cancers were investigated. Consenting family members underwent comprehensive evaluation, including physical examination, routine laboratory studies, pulmonary function testing, sputum cytology analysis, and lymphocyte karyotyping. In both families, the environmental influence of smoking and, to a lesser extent, occupational exposures were evident risks. Both families had members with multiple primary malignant neoplasms and probably radiogenic cancers, suggestive of inherent predisposition to environmentally induced neoplasia. Furthermore, one family had a newly recognized syndrome of limb and dental anomalies, and, independently, two members were carriers of a balanced translocation between chromosomes 13 and 14. Efforts were made to prevent further respiratory cancer deaths, to search for laboratory markers of risk, and to store blood and tissue specimens for assays in development.

Persistent or recurrent acromegaly. Long-term endocrinologic efficacy and neurologic safety of postsurgical radiation therapy.

As in other clinics, pituitary surgery was definitive treatment in less than 50% of cases of acromegaly treated at one institution over several decades. From 1965 to 1989, 24 acromegalic patients who had noncurative pituitary surgery received radiation therapy at the National Institutes of Health, with a basal human growth hormone level of greater than 5 ng/ml as the criterion for active disease. Using megavoltage irradiation, more than 60% of these patients stabilized at a normal hormonal range, and the overwhelming majority had decreasing growth hormone levels with time. No major side effects of irradiation were encountered except panhypopituitarism of varying degrees. The authors evolved a policy of surgery as the first option, followed by irradiation for patients with postoperative growth hormone levels more than 5 ng/ml.

Acute radiation effects on cutaneous microvasculature: evaluation with a laser Doppler perfusion monitor.

Laser Doppler perfusion monitoring is a noninvasive technique for measuring blood flow in epidermal microvasculature that makes use of the frequency shift of light reflected from red blood cells. Measurements in patients undergoing radiation therapy show increases in blood flow of ten to 25 times baseline at doses above 50 Gy, and increases are observed with doses as low as 2 Gy. Follow-up measurements show rapid decreases in flow levels after completion of therapy, but levels remain elevated even at 1 year.

Esophageal carcinoma following irradiation for breast cancer.

A patient previously irradiated for inner-quadrant breast cancer developed a midesophageal stricture that on repeated biopsies showed pathologic changes consistent with acute and chronic radiation injury. Eventually a focus of well-differentiated esophageal carcinoma was found in the stricture. The patient was the second in a series of 20 patients treated at Georgetown University Hospital, Medical Oncology Division, 1973-1978, for esophageal cancer, who gave a history of previous irradiation for breast carcinoma. This finding led to the review of related case reports, follow-up studies on irradiated spondylitic patients, and data from the Connecticut Tumor Registry on esophageal cancer following breast carcinoma. These data suggest that the modest increase in risk for esophageal cancer reported in studies of atomic bomb survivors is of clinical significance to patients receiving therapeutic radiation, and, that specifically, women irradiated for inner-quadrant breast cancer, in which the dose of radiation to the esophagus can be large, may be at risk for subsequent esophageal carcinoma.

Ependymoma, glioblastoma, and acute leukemia in a child.

A 5-year-old boy developed an ependymoma; 3 years later, after chemotherapy and radiotherapy, he developed glioblastoma multiforme and acute myeloblastic leukemia. His maternal grandmother had died at a young age of colon cancer. Since ependymoma is not known to predispose to other cancers, the unusual sequence of malignant disease may have been due to combined therapy in a susceptible host.