Pilot studies of superfractionated radiotherapy and combination chemotherapy in limited oat cell carcinoma of the bronchus.

There are sound radiobiologic and suggestive clinical rationale for superfractionating the radiotherapeutic regimens employed for the therapy of rapidly growing malignancies. Oat cell carcinoma of the bronchus is such a tumor. We report our experience combining aggressive systemic combination chemotherapy with superfractionated radiotherapy for the treatment of "limited" oat cell carcinoma of the bronchus. Overall, patient tolerance was satisfactory and a complete remission rate of 74% was achieved. It remains to be proven, in a prospective randomized fashion, whether this approach is superior to current conventional management.

Hypofractionated radiotherapy for the palliation of advanced pelvic malignancy.

Forty-two patients, with a variety of advanced pelvic malignancies, have been treated with a hypofractionated radiotherapy regimen. The most common schedule was 30 Gy in three fractions at monthly intervals. This has provided effective palliation with acceptable morbidity in the select patient group treated. The results in advanced rectal and ovarian tumors were particularly encouraging. The most effective dose/fraction and interfraction interval is, at present, under active investigation within our institution.

Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine.

PURPOSE: To develop dosing criteria for the use of L-buthionine-S-sulfoximine (active diastereoisomer) as a glutathione depletor in the clinic, using a pharmacodynamic and pharmacokinetic in vitro-in vivo approach. METHODS AND MATERIALS: In vitro: L-buthionine-S-sulfoximine uptake was determined in human glioblastoma cells (T98G) and NIH-3T3 cells using 35S-labeled drug. Dose response relationships were derived for inhibition of glutathione synthesis in CHO cells, and for depletion of glutathione in exponentially growing T98G and CHO cells, as a function of extracellular L-buthionine-S-sulfoximine concentration. Steady-state glutathione levels for CHO and NIH-3T3 cells were measured using an enzymatic assay, while glutathione synthesis rates in CHO cells were determined using a flow cytometric assay. In vivo: L-buthionine-S-sulfoximine biodistribution was determined in male nude mice carrying human glioblastomas (T98G) intracranially, using 35S-labeled drug infused subcutaneously by osmotic pump. Tissue glutathione levels were measured using an enzymatic assay. RESULTS AND CONCLUSION: The observed cellular uptake t1/2 of approximately 55 min, coupled with a previously reported, rapid in vivo clearance of buthionine sulfoximine, suggest that continuous infusion would be preferable to bolus dosing. Effective concentrations of L-buthionine-S-sulfoximine (24 h exposure), required to lower cellular glutathione content to 50% of control (EC50), were under 1 mM for both cell lines. The amount of L-buthionine-S-sulfoximine in tissues (estimated from 35S drug disposition) reached steady state within 8 h and was proportional to the rate of infusion. Brain tumors were depleted to approximately 50% of control glutathione by a infusion rate of 0.25 mumoles/h (25 g mice). At lower infusion rates an increase in glutathione content was noted in certain nude mouse tissues including brain tumor xenografts.

Modification of the aerobic cytotoxicity of etanidazole.

PURPOSE: To determine the feasibility of modifying the aerobic cytotoxicity of etanidazole without interfering with the tumoricidal action of radiation plus etanidazole. METHODS AND MATERIALS: The aerobic cytotoxicity of etanidazole was studied using two different models: (1) Induction of apoptosis in EL4 cells: apoptotic DNA fragmentation was analyzed by agarose gel electrophoresis following 24 h treatment with etanidazole alone or in combination with various modifiers. (2) Spinal cord neuronal loss in organotypic roller tube cultures: Survival of acetylcholinesterase positive ventral horn neurons was analyzed morphometrically following 72 h treatment with etanidazole alone or in combination with vitamin E succinate. RESULTS: Etanidazole (10 mM) induced apoptosis in EL4 cells. This effect was suppressed by 24 h treatment with TPA, IBMX, the free radical scavenger TEMPOL or vitamin E succinate. Vitamin E succinate also protected spinal cord cultures from etanidazole-induced neuronal loss. CONCLUSION: These results suggest that it might be possible to modify the neurotoxicity of etanidazole with agents that would not be expected to interfere with the tumoricidal action of radiation plus etanidazole.

Carcinoma of female urethra. Manitoba experience: 1958-1987.

Fourteen female patients with primary urethral carcinoma were treated at the Manitoba Cancer Foundation in the last twenty-nine years. The relationship of natural history to the stage, location, and therapeutic modality has been reviewed. A higher stage and length of urethral involvement affected prognosis negatively, whereas lower stage had a positive prognostic effect and location of tumor had no prognostic influence. Two patients with Stage C, who failed to received inguinal node radiotherapy, died of disease recurring in the inguinal area. Patients who received inguinal radiation (3 patients Stages B, C, and D1) had no regional recurrence. It is suggested that, for all female urethral carcinoma, bilateral ilioinguinal nodes be included in the radiation field. For radical treatment, iridium 192 insertion in combination with external beam treatment is recommended.

Heat production in microwave-irradiated thermocouples.

It has been known for some time that the irradiation of metallic thermometers by microwaves during clinical hyperthermia can lead to artifactual readings. We describe here a series of measurements in which this effect has been quantitatively studied. In particular, the data yield values for the conversion coefficient describing the rate of heat production per unit length of a thermocouple array per watt applied power which can be compared with the rate of heat production in the same volume of tissue. The degree of artifact in the temperature recording depends on the thermal resistance of the protective materials surrounding the array, and this thermal resistance has also been determined. It has been shown that measures taken to reduce the temperature artifact do not compromise the response time of the probe.

Matching photon and electron fields in the treatment of head and neck tumors.

Radiotherapy of head and neck tumors frequently involves joining photon and electron fields. In such situations narrow penumbras combined with relatively small positioning errors can lead to significant "hot" and "cold" spots in the vicinity of the join-up. The objective of this work was to devise penumbra spreading techniques which lead to a relatively uniform dose distribution in the join-up region of these fields and which reduce the effect of positioning errors on dose uniformity. A stepped edge attenuator was used to obtain a wider penumbra for the 4-MV x-ray beam and a Lucite scatterer was used for the 10-MeV electron beam. The resulting composite beam profiles from these "modified" abutting photon and electron fields are provided and the effects of positioning errors on dose uniformity across the junction are illustrated. These profiles are compared with those resulting from "unmodified" adjacent electron and photon beams.

Perturbation of the temperature distribution in microwave irradiated tissue due to the presence of metallic thermometers.

To date, satisfactory thermal dosimetry during the clinical application of localized hyperthermia can only be achieved using invasive thermometry. However the presence of commonly used metallic thermometers, such as thermocouples, may lead to the distortion of the temperature field due to self-heating of the probe under microwave irradiation. A computer simulation of the effect of this self-heating on the steady-state temperature distribution in plane-microwave irradiated homogeneous tissue has been undertaken and the significance of the effect for clinical hyperthermia dosimetry is assessed. The results indicate that a distortion of the temperature field in the neighborhood of the thermometer by several degrees can occur under adverse conditions.

Retrospective analysis of treatment of unresectable keloids with primary radiation over 25 years.

AIMS: The purpose of the study was to review retrospectively the role of primary radiotherapy for unresectable keloids. MATERIALS AND METHODS: Kilovoltage X-rays and mega-voltage electron beams were used to irradiate large bulky unresectable keloids. A total of 3750 cGy was given in five once-weekly fractions, over a period of 5 weeks. Eighty-six keloids in 64 patients were treated between 1977 and 2002. RESULTS: Ninety-seven per cent of this cohort had significant regression, and 3% had partial regression 18 months after completing radiotherapy. Both acute and long-term reactions were acceptable, and so far none of the patients have been reported as having cancer of any sort. Sixty-three per cent of the patients surveyed were very happy with the outcome of their treatment. CONCLUSION: Unresectable bulky symptomatic keloids can be satisfactorily treated with hypo-fractionated radiotherapy primarily using either kilovoltage X-rays or electron beams without significant short- or long-term side-effects.

Effect of superoxide dismutase on early radiation injury of lungs in the rat.

Early responses of lungs to a single radiation dose of 30 Gy were marked by an inflammatory reaction and the onset of pneumonitis within 4 weeks following hemithorax radiation in the rat. Superoxide dismutase reduced the severity of radiation lesions in lungs.

Combined modalities in the management of advanced head and neck cancers.

Split course radiation and kinetically based combinations of chemotherapy as suggested by Price, et al have been used for treatment of Stage III and Stage IV squamous cell carcinoma of the head and neck region. Twenty-nine patients were eligible for evaluation. Twenty-three out of 29 patients had complete remission of their primary tumor, three patients presented with N1 of which all had complete remission. Fourteen patients who presented with N2 neck nodes--three had complete regression and seven had partial response. Five patients who presented with lung lesion at the beginning; proved to be a second primary rather than metastases from the head and neck cancer. Subsequently, three patients had lung resection. At one year these three patients have remained free from recurrence from both the primaries. Toxicities had been noted due to combinations of two modalities which however had been within acceptable limits. Eighteen out of 29 patients had considerable persistent soft tissue edema in the irradiated area.

Long-term results of a pilot study for the treatment of advanced unresectable head and neck tumors by combination chemotherapy and split course radiotherapy.

The results of treatment of 30 patients with advanced unresectable squamous cell carcinoma of the head and neck (stage III and IV) are presented. These patients were treated in a pilot study using kinetically based combination chemotherapy and split course radiotherapy from July 1977 until December 1979. Twenty-three patients (76%) achieved a local response (53% complete and 23% partial) and the median survival was 16 months. The two-year survival was 43%. Although no significant increase in acute radiation morbidity was seen, 43% of the patients developed chronic symptomatic complications. Seven patients (23%) developed second primary cancers, of which five were bronchogenic carcinomas and two were esophageal carcinomas. The regimen adopted produced a high local control rate with permanent local control in 50% of patients treated, but this was achieved at the expense of a high chronic toxicity rate. The incidence of second primary malignancies, presumably because of on-going environmental factors, remains a continuing concern.

Management of oral mucosal dysplasia with beta-carotene retinoic acid: a pilot cross-over study.

Mucosal dysplasia in the head and neck region is recognized to be a precancerous lesion. Between January 1983 and December 1987, a pilot study was conducted at the Manitoba Cancer Treatment and Research Foundation to determine the effects of beta-carotene and cis-retinoic acid on mucosal dysplasias. Eighteen patients were treated with a "cross-over" regimen. The overall response to treatment was 61%, with 33.3% complete responses. Patients who smoked had a significantly better response than nonsmokers. The response rate for 9 of 11 smokers was 81.2%, and 2 of 7 nonsmokers or 28.6% responded to this protocol. The beneficial effect of these drugs should be established by prospective, randomized trial in high risk populations.