Influence of heat on the intracellular uptake and radiosensitization of 2-nitroimidazole hypoxic cell sensitizers in vitro.

The effect of elevated temperature (44 degrees) on the intracellular uptake of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole (MIS), and analogues more hydrophilic than MIS was studied in Chinese hamster ovary cells. It was found that the intracellular uptake of these compounds which enter cells by restricted passive diffusion can be enhanced approximately 4-fold when incubated at 44 degrees compared to the uptake at 37 degrees. Peak intracellular uptake (expressed as the ratio of intracellular concentration to extracellular concentration) following incubation of cells in 2 mM MIS was 100% at 44 degrees but only 25% at 37 degrees. Furthermore, a short-term nonlethal heat pulse (44 degrees for 15 min) with MIS present caused a 2-fold enhancement in uptake which was sustained for an additional 45 min at 37 degrees. This same nonlethal heat pulse was found to induce a similar enhancement in uptake even when MIS was added at subsequent time intervals at 37 degrees. The heat pulse induced a time-related enhancement of uptake at 37 degrees which increased for 1 hr and persisted for at least 6 hr. Finally, in vitro radiosensitization studies of hypoxic Chinese hamster ovary cells showed that the nonlethal heat pulse of 44 degrees for 15 min could greatly enhance the sensitization by low concentrations (0.5 mM) of MIS added after heating due to increased intracellular concentrations of the drug. MIS (0.5 mM) alone achieved a radiosensitization enhancement ratio of 1.29 (compared to irradiated hypoxic cells alone), while the addition of the short-term heat pulse, which had only a minor effect itself, achieved an enhancement ratio of 1.78.

Radiation therapy technology: manpower survey 1987.

A chronic shortage of radiation therapy technologists exists in the United States. This report presents the data obtained in a 1987 survey of all radiation oncology facilities identified by the Patterns of Care master list. Of the 1,142 questionnaires mailed, 52% were returned. The survey identified 2,328 credentialed (ARRT) and 554 non-credentialed technologists employed in radiation therapy. Of this total of 2,882, 2,141 were identified as staff technologists. A total of 1,186 megavoltage units were identified, giving a ratio of 1.8 technologist/megavoltage unit. Two hundred sixty open funded positions and 230 unfunded positions for radiation therapy technologists were identified. The report compares the results of this 1987 Radiation Therapy Technology Manpower Survey with the results of the three previous surveys conducted in 1975, 1977, and 1981. Whereas this comparison demonstrates that progress has been made, current trends in allied health education are expected to have a negative impact on recruitment into radiation therapy technology. Program directors report that the number and quality of applicants to all allied health education programs is declining, and this trend in radiation therapy technology is substantiated by a drop in the number of students enrolled in programs, from 970 in 1986-87 to 777 in 1987-88. Our discussion addresses the areas of new program development, recruitment, retention, innovative programs, and overseas recruitment.

Late effects of radiation on the eye and ocular adnexa.

A clinically useful classification system is suggested that can be used in prospective trials to evaluate the effects of radiation on the visual system. We review radiation-induced pathophysiological and clinical changes of the various ocular structures as well as dose-response data and management of ocular complications. The rationale for the classification scheme chosen is also discussed.

Increased risk of breast cancer in splenectomized patients undergoing radiation therapy for Hodgkin's disease.

PURPOSE: Second malignancies have been reported among patients who were treated by radiation therapy or chemotherapy alone or in combination. Studies have implied an increased risk of breast cancer in women who received radiotherapy as part of their treatment for Hodgkin's disease. This review was performed to determine if there is an association between splenectomy and subsequent breast cancer. METHODS AND MATERIALS: One hundred and thirty-six female patients with histologically proven Hodgkin's disease were seen in the Division of Radiation Oncology between 1962 and 1985. All patients received mantle or mediastinal irradiation as part of their therapy. The risk of breast cancer was assessed and multiple linear regression analysis was performed on the following variables: patient age, stage, dose and extent of radiation field, time after completing radiation therapy, splenectomy, and chemotherapy. RESULTS: Breast cancer was observed in 11 of 74 splenectomized patients and in none of 62 patients not splenectomized. The mean follow-up was 13 years in splenectomized patients and 16 years, 7 months in nonsplenectomized patients. Nine patients developed invasive breast cancer and two developed ductal carcinoma in situ. Splenectomy was the only variable independently associated with an increased risk of breast cancer (p < 0.005) in multiple linear regression analysis; age, latency, and splenectomy considered together were also associated with an increased risk of breast cancer (p < 0.01). CONCLUSION: Our data show an increased risk of breast cancer in splenectomized patients who had treatment for Hodgkin's disease. A multiinstitutional survey may better define the influence of splenectomy relative to developing breast cancer in patients treated for Hodgkin's disease. The risk of breast cancer should be considered when recommending staging laparotomy, and we recommend close follow-up examination including routine mammograms for female patients successfully treated for Hodgkin's disease.

Radiation therapy for macular degeneration: technical considerations and preliminary results.

PURPOSE: This study was undertaken to assess the toxicity and possible benefits from the administration of low-dose external-beam irradiation for Age-Related Macular Degeneration (ARMD). The premise of the treatment is that radiation induces regression and/or promotes inactivation of the subretinal neo-vasculature, resulting in reabsorption of fluid and blood thus reducing the risk for further leakage or bleeding, as well as subretinal fibrosis. Clinically, the beneficial effect could be translated into stabilization of visual acuity and prevention of progression of the wet type of ARMD with the possibility for some visual improvement. METHODS AND MATERIALS: Allegheny University Hospitals, Hahnemann, Department of Radiation Oncology, treated 278 patients prospectively beginning in January 1995 with low-dose irradiation for wet-type macular degeneration. Two hundred forty-nine patients were treated with a total dose of 14.40 Gy in eight fractions of 1.80 Gy over 10-13 elapsed days, and 27 patients with 20 Gy at 2 Gy per fraction over 12-15 days. The first two patients were treated to a total dose of 10.00 Gy in five fractions of 2.00 Gy. Patients were evaluated at 2-3 weeks and 2-3 months. A percentage (36.7%) of the patients had previously received laser treatments in the study eye, 21.9% once, 5% twice, 9.7% three or more. Subjective visual acuity and toxicity data was collected on all patients. RESULTS: At 2-3 weeks after treatment 195 patients (70%) retained their visual acuity without change, 68 patients (24.5%) stated they had improved vision, and 15 patients (4.8%) stated their vision continued to decrease. Two to 3 months after treatment, 183 patients (65.8%) had no change in their vision, 75 patients (27%) had an improvement in their vision, and 20 patients (7.2%) had a decrease in visual acuity. Transient acute reactions occurred in 14 of the 278 patients treated. CONCLUSION: Our observations in this group of 278 patients support the conclusion that many patients will have improved or stable vision after treatment with low-dose irradiation for age related wet type macular degeneration.

Radiotherapy for nasolacrimal tract epithelial cancer.

PURPOSE: Tumors of the lacrimal sac are rare and have traditionally been treated surgically. We investigated the use of irradiation for treatment. METHODS AND MATERIALS: Three consecutive patients with primary epithelial cancer of the nasolacrimal apparatus were treated with irradiation. A tumor dose of 52-66 Gy was delivered with conventional fractionation to fields limited to the primary site and immediately surrounding tissues. RESULTS: Local tumor control was achieved in all three patients. Two patients subsequently developed metastatic cervical adenopathy; both were controlled with irradiation to the neck. One of these two died of distant metastases. Two patients are alive and well at 13 years and at 26 months. CONCLUSION: We conclude that epithelial lacrimal sac tumors are controllable by radiation therapy and with a good cosmetic result. Poorly differentiated lesions require elective cervical nodal irradiation.

Induction and repair of DNA double-strand breaks.

Induction and repair of DNA double-strand breaks (DSBs) was measured using a pulsed-field gel electrophoresis system. A cell line of methotrexate-resistant EMT-6 cells that contain numerous double-minutes (DMs) 3 million base pairs in size was employed. The electrophoretic mobility of these DMs depends on whether they have zero, one, or more than one DSB. With no DSBs the DMs remain as circles and are trapped in the origin of electrophoresis, but with one DSB the DMs migrate as a discrete band and can be detected easily through hybridization with a gene-specific probe. Using a clamped homogeneous electrical field apparatus, the induction of DSBs in the 1.5 to 12 Gy X-ray dose range is studied and is shown to be linear. Double-strand break repair following 7.5 Gy is studied, and is shown to be exponential. The kinetics of both induction and repair of DSBs induced in DM DNA was compared to the induction and repair of DSBs in chromosomal DNA and is shown to be similar. The kinetics of repair of DSBs following 7.5 Gy for cells embedded in agarose and cells in suspension is shown to be similar.

Orbital rhabdomyosarcoma: treatment or overtreatment.

In 1972, the Intergroup Rhabdomyosarcoma Study standardized the classification and treatment of orbital rhabdomyosarcoma. It established chemotherapy with external beam radiotherapy as the standard of treatment, yet there was no comparison to treatment with external beam radiotherapy alone. We retrospectively examined the charts of patients with orbital rhabdomyosarcoma treated solely with external beam radiotherapy for the following data: age at diagnosis, gender, tumor recurrence, and tumor-related mortality. We followed 24 patients (mean follow-up 7.9 years) treated with external beam radiotherapy alone. The average age at diagnosis was 5.5 years; there were 15 males and 9 females. Three patients (12.5%) suffered tumor recurrence and there was one (4.2%) tumor-related death. When compared to the Intergroup Rhabdomyosarcoma Study, results suggest that chemotherapy with external beam radiotherapy may offer no advantage to external beam radiotherapy alone for the treatment of orbital rhabdomyosarcoma.

Treatment results of combined high-dose preoperative radiotherapy and surgery for oropharyngeal cancer.

Fifty eight patients receiving planned high-dose preoperative radiotherapy followed by en bloc oro-mandibular-cervical resection for oropharyngeal cancer were reviewed. These patients received continued close observation and care from both the Otolaryngology and Radiotherapy services. In light of the ongoing controversy of preoperative vs. postoperative radiotherapy, we present our data demonstrating the value of preoperative radiation. An overall tumor control rate of 66% was achieved, with an adjusted survival rate of 62%. This was not only for early lesions, but also in patients having advanced (T3, T4) tumor and/or nodal disease (N1-4). These figures are somewhat higher than expected from the literature. A review and discussion of the surgical complications are also presented.

High-dose hemithorax irradiation in a patient with recurrent thymoma: a study of pulmonary and cardiac radiation tolerance.

Malignancy spread throughout a hemithorax without distant metastasis poses a difficult therapeutic challenge. Irradiation is often not considered because of the risk of pulmonary and cardiac toxicity. We report on a patient with thymoma recurrent throughout the left pleural cavity. Disease progressed despite chemotherapy, and subsequently a radical course of radiotherapy (6,600 cGy) was delivered to the entire hemithorax. Tumor regressed markedly by the completion of radiotherapy. Although tumor regrowth was noted 1 year after radiotherapy, the patient remained markedly improved symptomatically until shortly before her death 2 years after radiotherapy. Pulmonary function tests at 1 year (forced expiratory volume of the first second and forced vital capacity) were similar to pretreatment values, and cardiac function at 2 years remained essentially normal. High-dose hemithorax irradiation may be a consideration in select cases.

Long-term evaluation of postorchiectomy radiotherapy for stage II seminoma.

PURPOSE: To determine survival, long-term tumor control, and the effects of irradiation for stage II seminoma. MATERIALS AND METHODS: Forty-five patients with stage II testicular seminoma were treated between 1966 and 1989. There were 31 patients with stage IIA disease and 14 with stage IIB disease. All patients underwent orchiectomy followed by iliac and paraaortic irradiation (median dose: 30 Gy), with 37 patients receiving prophylactic mediastinal and supraclavicular irradiation (median dose: 30 Gy). Follow-up ranged from 6 months to 20.6 years, with a median of 9.4 years. RESULTS: Uncorrected survival was 98% at 5 years, 84% at 10 years, and 79% at 15 years. Survival corrected for intercurrent disease was 98% at 5, 10, and 15 years. Five patients developed recurrences with four successfully salvaged by chemotherapy and/or irradiation. There were no serious acute toxicities, and no late complications have developed from infradiaphragmatic irradiation. Supradiaphragmatic irradiation was associated with an increased risk of coronary artery disease compared to the age-matched general population. CONCLUSION: Radiotherapy remains an effective treatment for stage II testicular seminoma, with a 98% adjusted survival rate at 15 years, without serious acute toxicity. Supradiaphragmatic irradiation should not be used in stage IIB patients for whom salvage chemotherapy is an option.

'Full dose' reirradiation of human cervical spinal cord.

With the progress of modern multimodality cancer treatment, retreatment of late recurrences or second tumors became more commonly encountered in management of patients with cancer. Spinal cord retreatment with radiation is a common problem in this regard. Because radiation myelopathy may result in functional deficits, many oncologists are concerned about radiation-induced myelopathy when retreating tumors located within or immediately adjacent to the previous radiation portal. The treatment decision is complicated because it requires a pertinent assessment of prognostic factors with and without reirradiation, radiobiologic estimation of recovery of occult spinal cord damage from the previous treatment, as well as interactions because of multimodality treatment. Recent studies regarding reirradiation of spinal cord in animals using limb paralysis as an endpoint have shown substantial and almost complete recovery of spinal cord injury after a sufficient time after the initial radiotherapy. We report a case of "full" dose reirradiation of the entire cervical spinal cord in a patient who has not developed clinically detectable radiation-induced myelopathy on long-term follow-up of 17 years after the first radiotherapy and 5 years after the second radiotherapy.

Local excision and radiotherapy for cancer of the oral tongue. A preliminary report.

A group of 18 patients with squamous cell carcinoma of the mid one-third of the tongue was treated by local resection and planned postoperative radiotherapy between 1976 and 1980. Tumors 0.5 cm or greater in thickness were included; no patients had cervical adenopathy. Six were categorized as T1, 10 as T2 and two as T3. In eight patients, histologic review showed tumor extension at or near the resection margin, despite a tumor-free margin at frozen section, while in 10 patients the margins were clear. Local tumor control was achieved in 16 patients (89%). Two failures were evident within 3 months after completion of treatment. The relatively short follow-up of such a small series limits the conclusions from this preliminary study, but the excellent results thus far merit further study.

Report of the 1997 SCAROP survey on resident training. Society of Chairmen of Academic Radiation Oncology Programs.

RATIONALE AND OBJECTIVES: Members of the Society of Chairmen of Academic Radiation Oncology Programs (SCAROP) were surveyed in November 1997 to evaluate the current status of radiation oncology training in the United States and to help determine how it should be carried out in the coming decade. MATERIALS AND METHODS: A detailed questionnaire was sent to all members of SCAROP; 68 of 82 questionnaires were returned, for a response rate of 83%. RESULTS: The responses to the survey show a serious shortage of radiation oncologists in university settings, despite an apparent surplus in private practice. Although recent changes in health care have added additional clinical responsibilities for radiation oncologists in university practices, approximately 75% of the chairpersons answering the survey continue to give their faculty protected time for research. Even with additional research and teaching responsibilities, the average radiation oncologist in university practice saw 206 patients per year in 1997, a number similar to that reported by the Patterns of Care Study for radiation oncologists overall. Approximately two-thirds of respondents believe that academic chairs should strive to have all clinical faculty members participating in research. Nevertheless, most think that basic research is better performed by dedicated researchers with PhD degrees rather than radiologists with MD degrees. Most respondents believe that the training programs adequately prepare radiation oncologists for a career in academic medicine but do not provide good training in research. Eighty-four percent agreed that resident performance on the American Board of Radiology examination should be considered in the accreditation of residency programs in radiation oncology but should not be the major criterion. CONCLUSION: There is a shortage of academic radiation oncologists in the United States despite the large number of radiation oncologists completing training. This probably is due to a variety of factors, including a relatively small pool of candidates for academic positions, increasing demands for performance from academic physicians (to see more patients, perform research, publish, write grants, and teach), and competition from the private sector for recruitment of these individuals.

Carcinoma of the anterior tongue.

We have reviewed 126 patients with squamous cell carcinoma of the anterior tongue. Our experience suggests that carcinoma of the anterior tongue is a highly aggressive disease. It is no less aggressive and dangerous than carcinoma of the posterior tongue. The clinically negative neck is a problem. Many clinical stage I and II cancers are, in fact, stage III when analyzed by the pathologist. This difficulty in clinical staging results in a significant management problem when stage III carcinomas are treated as stage I and stage II disease. Management, if it is to cure, must be aggressive. An adequate, wide surgical resection will control early carcinoma of the anterior tongue. Advanced cancers of the anterior tongue, clinical stages III and IV, should be widely excised; the cervical lymph nodes on the side of the primary lesion must be treated by surgery and radiation therapy. Treatment of the opposite side of the neck is indicated based on a high rate of metastases to contralateral lymph nodes in this series. Those patients treated with irradiation who had recurrence did so predominantly at the primary site of disease. Patients treated surgically tended to have recurrence in the regional cervical lymphatics.

High dose preoperative irradiation for advanced laryngeal-hypopharyngeal cancer.

Combined therapy, consisting of 5000 rads delivered in five weeks by total laryngectomy +/- radical neck dissection, was compared with treatment by irradiation (6000-7000 rads) with surgical salvage when clinically possible for radiation failure. Patients were categorized according to site of primary cancer (glottic, supraglottic and pyriform sinus) and staged (T, N, M). Survival was equally good in the two programs for glottic and supraglottic lesions, N0 or N1. The combined treatment program was judged superior for supraglottic and pyriform sinus lesions, N2 or N3.