Fractionated stereotactic radiotherapy for acoustic neuromas: long-term outcomes.

AIMS: Acoustic neuromas are rare, benign intracranial tumours. There are a variety of treatment options, with no clear optimal management strategy and wide variation in treated outcomes. We report the outcomes from a 15 year cohort of patients treated at our centre using fractionated stereotactic radiotherapy (52.5 Gy in 25 fractions). MATERIALS AND METHODS: We analysed a retrospective case series. Patients were identified from patient records and a retrospective review of case notes and imaging reports was undertaken. We assessed tumour response using RECIST criteria and recorded toxicity. Progression-free survival was estimated using the Kaplan-Meier method. The study was conducted according to the STROBE guidelines. RESULTS: In total, 93 patients were identified; 83 patients had follow-up data, with a median follow-up period of 5.7 years. The overall control rate using RECIST criteria was 92%. Data on complications were available for 90 patients, with six (7%) experiencing a reduction in hearing, one (1%) developing trigeminal nerve dysfunction and one (1%) a deterioration in facial nerve function. Other toxicities included four (4%) patients who developed hydrocephalus, requiring the placement of a shunt and one (1%) patient who developed radiation brainstem necrosis. After further evaluation this patient was deemed to have been treated within acceptable dose constraints. CONCLUSION: These data suggest that a good control rate of acoustic neuromas is achievable using fractionated stereotactic radiotherapy to a dose of 52.5 Gy in 25 fractions. Toxicity is considered acceptable but the episode of radiation brainstem necrosis remains of concern and is the subject of further work.

Incidence of cataracts after single fraction total body irradiation: the role of steroids and graft versus host disease.

Eighty-eight patients who received single fraction total body irradiation (sfTBI) as part of their conditioning for allogeneic BMT have been evaluated for the risk of cataract formation. Thirty-eight (43%) have developed cataracts; 11 required surgery. With 9.5-13.6 years follow-up (median 10.7 years), all 12 recipients of unmanipulated marrow allografts have developed cataracts; the actuarial risk of needing surgery was 32 (+/- 18%, 95% confidence intervals (CI)). Ten of these 12 required high-dose steroids (prednisolone > 1 mg/kg/day) for the treatment of GVHD. Seventy-six patients received T cell-depleted allografts; 14 of 76 required post-transplant immunosuppression with high-dose steroids. With 1-9.4 years follow-up (median 5 years), the actuarial risk of cataract formation in T cell-depleted allograft recipients is 72% (+/- 52% CI), the actuarial risk for needing surgery is 20% (+/- 9% CI). Recipients of sfTBI and non-T cell-depleted allografts had a significantly greater risk of developing cataracts (p = 0.003, long rank test) and of needing surgery (p < 0.05, log rank test) than patients receiving T cell-depleted BM. Cataracts occurred more frequently in patients requiring post-transplant immunosuppression with steroids (relative risk 2.12, p < 0.01 log rank test).

Results of a randomized, double-blind comparative study of ondansetron and metoclopramide in the prevention of nausea and vomiting following high-dose upper abdominal irradiation.

Ondansetron is a 5-hydroxytryptamine 3-receptor antagonist which has shown activity in the prevention of cytotoxic-induced emesis. Preliminary non-randomized studies also indicated efficacy in preventing sickness following radiotherapy. The present study was therefore undertaken to compare the efficacy and safety of ondansetron (8 mg tds orally) and metoclopramide (10 mg tds orally) in preventing sickness after single-exposure radiotherapy treatments of 8-10 Gy to the upper abdomen. Of 82 evaluable patients 38 received ondansetron and 44 metoclopramide. On the first day after irradiation vomiting or retching was prevented in all but one of the patients on ondansetron whereas metoclopramide achieved complete control of these symptoms in only 46% of subjects (P less than 0.001). Similarly nausea was significantly better controlled by ondansetron in the first 24 hours after treatment (P = 0.001). Complete or major control of vomiting or retching was maintained for 92%-100% of patients on ondansetron during the five days of the study period. In the metoclopramide group the proportion of patients with equivalent control improved from 70% on day 1 to 95 on day 5. Both drugs were well-tolerated.

Radiation-induced chondrocalcinosis of the knee articular cartilage.

A case of a middle-aged man with symptomatic, localised chondrocalcinosis of the knee following irradiation is described. Cartilage damage induced by radiotherapy should be added to the list of local factors which can predispose to chondrocalcinosis.

Seminoma of the testis with bone involvement: a report of three cases.

Three cases of seminoma metastasising to bone and treated with radiotherapy are reported. All three patients are alive and disease-free between 6 and 16 years after diagnosis. The value of radiotherapy in this situation should be borne in mind.

Lung damage in mice from cyclophosphamide and thoracic irradiation: the effect of timing.

The development of lung damage in mice following thoracic irradiation is enhanced by cyclophosphamide (CY). CY was given at various times from 28 days before to 28 days after irradiation. Although increased damage was seen at all times, the extent showed marked variation according to the time interval. The most marked variations were seen when CY was given within 24 hours of irradiation; maximal enhancement was seen when CY was given before or with irradiation and minimal response when given 12 hrs before or 12 hrs after irradiation. It may therefore be prudent for the clinician to avoid such close time intervals between cytotoxic drugs and irradiation, unless a specific time-related therapeutic gain can be exploited.

The effects of anesthetics and misonidazole on the development of radiation-induced lung damage in mice.

The measurement of breathing frequency as a functional end-point of radiation-induced lung injury in mice allowed two phases of damage to be discerned; the first was manifest at 12-20 weeks after irradiation, the second beyond 28 weeks. Anesthesia by pentobarbitone sodium or steroids gave significant radioprotection of the lung during the early pneumonitic phase. Addition of the hypoxic cell sensitizer misonidazole removed the protective influence of the anesthetics but did not sensitize the lungs of unanesthetized mice. No anesthetic protection was detected for the late response, showing evidence for dissociation between early and late lung damage. The degree of epilation was measured on the dorsal thoracic region of the same mice. Protection by anesthetics and its reversal by misonidazole was also demonstrated. These results provide a warning of potential hazards in the laboratory evaluation of chemical radiosensitizers. The use of anesthetics at the time of irradiation could lead to an exaggerated enhancement of normal tissue damage.

Bleomycin and radiation-induced lung damage in mice.

Bleomycin-induced lung damage was assessed using both a functional end-point and mortality. The extent of lung damage was found to depend on the schedule, mode of administration and dose of the drug. Greater damage occurred following twice-weekly administration than when the same dose was given as a single injection. Intravenous administration resulted in greater damage than intraperitoneal administration. When bleomycin was given with thoracic irradiation lung damage occurred earlier and at lower radiation doses than with radiation alone. Similar responses were obtained whether bleomycin was given four weeks before, with or four weeks after irradiation. Thus although there was enhanced damage from the combined treatment, there was no evidence of a time-dependent interaction.

Dose-dependence of the time of appearance of lung damage in mice given thoracic irradiation.

Male CBA mice were given X-radiation to the thorax in the range 7 to 23 Gy and their response was quantified by measuring ventilation rate and carbon monoxide uptake at intervals up to 2 years thereafter; their survival was also documented. The two functional end-points were similarly sensitive indicators of lung damage. Radiation damage was not observed below 10 Gy. As radiation dose was raised above this level there was a rapid shortening of the time to the appearance of damage and subsequent death. At a dose of 15 Gy the median survival time was 14 weeks but raising the dose above this level only slightly reduced the survival time. The way in which the time of survival after lung damage depends on dose is an important characteristic of the development of radiation-induced lung damage which should be considered when examining factors that may influence the development of radiation-induced lung damage.

A kinetic model for the pathogenesis of radiation lung damage.

The development of radiation-induced lung damage can be explained by a kinetic model, based on the assumption that this damage becomes manifest only when a critical proportion (K) of essential cells have ceased to function, and that the rate of loss of these cells following irradiation is linear and dose-dependent. The kinetic model relates the surviving fraction to the time to manifestation of radiation-induced lung damage and to constants, K and the cell cycle time, T. Predictions made from the model about the nature of the response to irradiation are, for the most part, fulfilled. The model can also be used to interpret the response to combined treatment with irradiation and cytotoxic drugs, including the much earlier manifestation of lung damage sometimes seen with such treatment.

Clinical objectives and normal tissue responses in combined chemotherapy and radiotherapy.

It is clear that the risk of toxicity to normal tissues in combined therapy is reduced by separating drug administration and radiation exposure in time. The short-term interaction of drugs and radiation aimed at producing enhanced tumour cell kill is difficult to demonstrate in vivo in animal experiments and unlikely to be important in clinical practice. Increased toxicity of normal tissues in man has been manifest both in terms of early and late reactions and probably also in carcinogenesis. In the latter context choice of drug and possibly sequencing may be important in minimising the risk of tumour induction. There are few experimental studies examining moderately long time intervals between drug and radiation exposure. The administration of chemotherapy prior to irradiation may be less toxic than the converse sequence, although clinical data supporting this contention are limited at the present time.

Cyclophosphamide-induced lung damage in mice: protection by a small preliminary dose.

Cycylphosphamide (Cy) produces an interstitial pneumonitis in CBA mice. The extent of the lung damage has been quantified by measuring the increase in ventilation rate over 6 weeks after an i.p. injection of Cy 200, 250 and 300 mg/kg. A dose-dependent response was found. When a preliminary ("priming") dose of Cy at 50 mg/kg was given 7, 9 or 14 days before a single large dose of 250 mg/kg, lung damage was reduced, as shown by a smaller increase in ventilation rate than in those receiving 250 mg/kg alone, and this difference was significant (P less than 0.01) in the Day-14-and highly significant (P<0.001) in the Day-7-"primed" groups. When primed less than 7 days before, there was a relative increase in ventilation rate, which was statistically significant (P less than 0.01) in the Day-1-primed group. Similar effects were also seen in the survival of the mice.

Lung damage from cytotoxic drugs.

Bleomycin, busulphan, and methotrexate are by far the commonest cytotoxic drugs to cause interstitial pneumonitis. However, many other cytotoxic drugs have been reported to produce similar lung damage. Combined effects of these drugs, and of the drugs with other agents that cause lung damage, such as oxygen and radiation, may result in enhancement of lung damage. Early diagnosis, made possible by awareness of this complication and its correct investigation, may reduce severe morbidity and mortality. In some instances, factors that predispose to lung damage are known, and these have been studied in experimental animals.

Seminoma in Marfan's syndrome.

A patient with a testicular seminoma and Marfan's syndrome is described. The association is unlikely to be by chance alone, and an explanation in terms of either an associated congenital defect, or a minor chromosomal anomaly, is discussed.