An animal model of prophylactic cranial irradiation: histologic effects at acute, early and delayed stages.

Wistar rats (body wt. 200 g) were subjected to a fractionated course of radiation similar to that used in prophylactic brain irradiation for small cell carcinoma of the lung (2000 cGy in 5 fractions over 5 days with 60Co). Effects of this regimen were assessed by histologic examination of brain sections at 1 week, 1 month and 6 months post-irradiation. With conventional stains there were no apparent differences between control and irradiated brains at any of the post-irradiation intervals. Immunohistochemistry for neurotransmitter synthetic enzymes tyrosine hydroxylase and glutamate decarboxylase, as well as histochemistry for acetylcholinesterase, failed to uncover any changes in the irradiated animals. Immunohistochemistry for glial fibrillary acidic protein, an astrocyte marker, also showed no differences in the irradiated groups. However, an antibody against a major histocompatibility complex, class II antigen (OX-6) revealed a microglial response in grey and white matter beginning at 1 month and increasing up to the 6 month post-irradiation interval. The neuroanatomical basis for this microglial response was suggested by the results of silver stains for nerve axons, which revealed axonal loss in striatal white matter bundles in a pattern implicating vascular insufficiency.

Supervoltage radiotherapy for Graves' ophthalmopathy: CCABC technique and results.

A treatment technique employing retrobulbar supervoltage radiotherapy (XRT) in Graves' ophthalmopathy is described. Twenty-eight patients have been treated and followed between 1980-1983. Twenty-six of 28 patients (93%) showed some response, with 19/28 (68%) having a good to excellent response. Four of 28 (14%) had recurrent symptoms post-XRT. Soft tissue signs and symptoms were relieved and disease progression arrested in the majority of patients, but proptosis and ophthalmoplegia responded poorly. High dose corticosteroids have generally been the alternative form of therapy for this disease. Post-XRT, 24/28 (86%) of patients have had no further steroid requirements, and been spared the associated complications. Treatment was well tolerated, with only five patients (18%) demonstrating a transient worsening of symptoms which settled entirely within 2 weeks. No long-term complications have been encountered. Eleven patients had post-XRT CT scans which were compared to pre-treatment scans and clinical response. Nine of 11 patients (82%) had CT changes in general agreement with the observed clinical response, but the degree of involvement seen on the initial CT scan was not predictive of response nor the risk of relapse. XRT with the described technique is felt to be an effective, safe, and practical approach to the disabling and disfiguring complications of severe Graves' ophthalmopathy.

Superfractionated radiotherapy in grade III, IV intracranial gliomas.

Preliminary results of superfractionation in the treatment of glioblastoma led to a randomized trial consisting of 76 patients. All patients received whole brain irradiation followed by a 1000 cGy boost to the primary site. Thirty-four patients received standard daily treatment to 4000 cGy, whereas 42 patients received superfractionated radiation, treating three times a day to a total dose of 4760 cGy. No significant difference was found between the 5-year survival of the superfractionated group and the standard treatment group. Early reactions were greater for superfractionation whereas late effects were less.

Pions, Vancouver.

Clinical treatments at TRIUMF started in November, 1979. Ten patients with malignant subcutaneous nodules had 14 lesions treated with pions and 37 other nodules treated with 280 kV X rays. Three different fractionation regimens were used with X ray doses spanning the expected RBE range of pions. The RBE for pions for acute skin reaction for 10 fractions had a mean value about 1.5, while for 3 fractions it was 1.3 maximum. No dissociation of acute and late skin effects was seen with follow-up to 27 months after treatment. Phase 1-2 studies of Pion-Boost Therapy for patients with glioblastoma multiforme will begin in May, 1982. These will be followed in August with treatments of advanced pelvic malignancies using pions only. The existing beam line at TRIUMF will be upgraded and commitments have been given to go to higher beam currents. As a result, the dose rate should increase by a factor of at least two, allowing treatment of clinically relevant volumes in acceptable times by 1983-1984.

Effect of acetylsalicylic acid on radiation and cosmetic results after conservative surgery for early breast cancer: a randomized trial.

BACKGROUND AND PURPOSE: Acetylsalicylic acid (ASA) can reduce the incidence of stroke and myocardial infarction by inhibiting platelet-fibrin thrombi in small blood vessels. To determine if ASA could reduce late effects of radiation therapy mediated by damage to small blood vessels, a prospective, placebo-controlled, double-blind trial was conducted in women with early breast cancer, receiving radiotherapy to the conserved breast. MATERIALS AND METHODS: Cosmetic outcome and late radiotherapy effects were recorded prospectively for 186 women with T1 or T2, pathologically node-negative breast cancer treated with breast conservation and randomized to receive ASA (325 mg daily) or placebo for 1 year from the start of radiation therapy. Radiation was a tangent pair to the breast alone delivering a modal dose of 44 Gy in 16 daily fractions in 22-25 days. RESULTS: Median follow-up is 6.5 years. The use of ASA has not had any effect on the acute (erythema, edema or discomfort) or late (induration, telangiectasia) effects of radiotherapy (all P > 0.10), the patients' or physicians' assessment of the cosmetic outcome (all P > 0.25) or rates of breast recurrence (P > 0.25). CONCLUSION: ASA cannot be recommended to improve the outcome of radiotherapy complementing breast conserving surgery.

Neoadjuvant hormone therapy and external beam radiation for localized prostate cancer: Vancouver Island Cancer Centre experience.

OBJECTIVES: To evaluate the effects of neo-adjuvant hormone therapy (NAHT) given prior to radiation in patients with clinically localized adenocarcinoma of the prostate. METHODS: Six hundred nine patients were treated between 1992 and 1997 with NAHT prior to radiation therapy. Clinical stage, presenting PSA and Gleason score were examined for influence on outcome. Time to post radiotherapy failure was defined from the first assessed PSA value over 4 microg/L at follow-up. Radiation therapy was confined to the prostate and seminal vesicles. Median follow-up was 2.6 years. RESULTS: PSA disease free survival (PDFS) decreased with increasing cancer risk factors (p <.0.0001). The overall duration of NAHT was significant with patients receiving >8 months having a lower failure rate than those on therapy for <3 months (p <0.0001). The PSA prior to starting radiation correlated with outcome, a PSA <=0.1 microg\L having a better PDFS than those with a PSA >=4 microg\L (P <0.0001). NAHT for >8 months gave improved PDFS in intermediate grade Gleason score 5-7, (n = 256, p <0.0001), high grade Gleason score 8-10 (n = 80, p =0.005), but not in low grade, Gleason score <=4. CONCLUSION: Neo-adjuvant hormone therapy for >8 months offers prolonged PSA disease free survival in patients with less well differentiated tumors, Gleason score >4. Clinical trials are required to confirm this.

Neoadjuvant hormone therapy and radical radiotherapy for localized prostate cancer: poorer biochemical outcome using flutamide alone.

Since a recent meta-analysis of non-steroidal anti-androgen therapy in metastatic prostate cancer concluded that survival was worse compared with medical or surgical androgen withdrawal, we analyzed our experience with flutamide monotherapy and other forms of neoadjuvant hormone therapy (NHT) prior to radiation therapy in clinically localized prostate cancer. A total of 45 patients received flutamide and 328 patients received other NHT. Flutamide patients had higher PSA levels at diagnosis and shorter duration of treatment, which could bias the results against flutamide monotherapy. Kaplan Meier analysis of PSA -- disease free survival showed significantly poorer outcome with flutamide monotherapy. Multivariate analysis supported this conclusion. Until equivalence to other forms of NHT is shown, we do not recommend flutamide monotherapy prior to radical radiation. A prospective randomized trial would be necessary to confirm this conclusion.

Three dimensional radiation therapy planning using light projection of CT scans.

A simple, quick, accurate method of transferring CT scan images on to radiotherapy planning films is described using a modified overhead projector with variable magnification properties.

Preliminary report: acetylsalicylic acid therapy in the treatment of complications following abdominal radiation.

A group of 10 patients with complications following pelvic irradiation were treated with acetylsalicylic acid (ASA). Epithelial ulceration was healed in four of six patients and improved in one. Radiation enteritis was decreased or abolished in all patients who remained on ASA.

Recent observations on the ultrastructure of human urothelium. 1. Normal bladder of elderly subjects.

An electron microscopic study of normal bladder urothelium of elderly patients ranging in age from 61 to 82 years has shown the occurrence of unusually thin regions consisting of either one or two layers of undifferentiated cells interspersed between 3--4 cell layers thick regions. A morphometric study has confirmed the existence of a pattern of cytodifferentiation in cells of the thick region. The generally microvillous nature of the luminal surface is attributed to incompletely differentiated cells that have come to occupy the superficial layer. The lack of thickened and/or asymmetric membrane plaques in luminal plasma as well as the dearth of characteristic precursor vesicles in the cytoplasm are also explicable in terms of a failure of normal cell differentiation. It is suggested that the unusual features noted are consequences of tissue ageing rather than prognostic of cancer. There are indications that the aged urothelium may be prone to increased leakiness and the bladder tissues may therefore be at greater risk from urine-borne chemicals and carcinogens.

Observations on the ultrastructure of human urothelium: the response of normal bladder of elderly subjects to hyperthermia.

An electron microscopic study of normal bladder urothelium of elderly subjects treated by hyperthermic perfusions has shown that the tissue responds, sooner or later, in every instance by desquamation. There is no evidence of cell death prior to desquamation although various organelles undergo structural alterations. Mitochondria are especially prone to suffer varying degrees of damage. A short heat shock has revealed differences in the initial response of the thick and thin regions of bladder urothelium known to occur in elderly subjects. After a long, fractionated treatment, regeneration is evident within 3 days of the end of treatment, and follow-up biopsies have revealed a hyperplastic urothelium within 10 to 12 weeks. The constituent cells show signs of cytodifferentiation at this time but it remains unknown when an ultrastructurally normal urothelium with characteristic cell layers will be restored. The various treatments in this study suggest that the stem cells in the epithelium are unaffected by the levels of hyperthermia employed and that their unimpaired proliferative capacity ensures regeneration of the urothelium.

Clinical effects of whole-body hyperthermia in adnanced malignancy.

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.

The treatment of adult supratentorial high grade astrocytomas.

From 1 January, 1982 until 31 December, 1987 260 adult patients were referred to the Cancer Control Agency of B.C. with high grade supratentorial astrocytomas. Multifocal disease on presentation was present in 17 cases (6.5%). Their survival is poor and whole brain radiotherapy is required. All other cases had unifocal disease, but eight did not receive radiotherapy. The 235 cases who received radiotherapy were subject to univariate and multivariate analyses according to extent of surgery, age, Kernohan and WHO grading, Karnofsky performance status, whole brain treatment, partial brain treatment, total dose and neuroret. Age is an extremely important predictor of survival (P approximately equal to 0). The pathologic appearance of glioblastoma (WHO grade) as well as the Karnofsky performance status were also important independent factors in predicting survival (P = 0.016, 0.027 respectively) on Cox multivariate analysis. Dose and neurorets were significant factors only in cases where the performance status was not recorded, suggesting that dose was selected according to the patient's condition and age. In this analysis it was found that localized radiation fields may be used rather than whole brain without jeopardizing survival.

Hyperthermic perfusion of the distended urinary bladder in the management of recurrent transitional cell carcinoma.

The clinical and histological changes following hyperthermic perfusion of the distended urinary bladder have been studied in 13 patients with transitional cell carcinoma, persistent after radical radiotherapy. Continuous epidural anaesthesia was necessary to achieve a constant state of bladder relaxation during irrigation of the distended bladder. This form of hyperthermic perfusion of the bladder was effective in arresting uncontrollable haemorrhage from bladder tumours and may be of value in the treatment of this complication. Perfusion at an outflow temperature of 44 degrees C for 4 hours caused tumour necrosis. It was, however, associated with damage to the vasculature of the bladder and frequency of micturition which persisted after mucosal recovery. Perfusion at 43 degrees C also caused tumour necrosis and the after effects were less severe.

Preparatory clinical studies of Pi-mesons at TRIUMF.

Eighty patients have been treated with Pi-mesons (pions) at TRIUMF between 1979-1984. The patients had tumors rarely curable by standard methods and had no prior radiotherapy. The distribution by site included skin, metastatic nodules (13), brain, glioblastoma multiforme (32), pelvis, rectosigmoid (15), prostate (12), bladder (7), and ovary (1). The studies involve serial escalations of pion dose until maximum tissue tolerance is reached, monitoring the response at each dose increment. Sites were chosen for study where lack of local control is a significant cause of treatment failure with conventional radiation therapy. The low dose rate and the available beam access at TRIUMF limit the number of patients treated and the volume treatable. A 3-D treatment planning program is in use, and a 3-D display of the dose distribution delivered in brain tumor treatments has been developed using the PET scanner. In practice, new methods introduced for measurement of tissue response include tumor growth delay curves, fine-needle biopsy mapping, and PET scanning of brain tumors. The use of endoscopic assessment of the rectosigmoid region is emphasized. Treatment results of glioblastoma multiforme show that the median survival for patients treated to 125 pion cGy/fx is in the range of 187-198 days; for patients receiving 170 cGy per dose/fraction (fx) the range is 290-315 days, and for those receiving 200-220 cGy/fx the median survival is in excess of 290 days. For pelvic malignancies the local control obtained with doses of 2500 cGy or less was 50% in 12 assessable patients; it was 75% in 20 patients who had 3000 cGy or more.(ABSTRACT TRUNCATED AT 250 WORDS)