Permanent prostate brachytherapy: a century of technical evolution.

PURPOSE: To summarise the practical aspects of the development of techniques of interstitial permanent prostate brachytherapy (PPB) implantation. Prostate brachytherapy dates back to Pasteau's publication in 1913 describing the insertion of a radium capsule into the prostatic urethra to treat carcinoma of the prostate. Various implantation methods were employed but with unsatisfactory results until the development of the transrectal ultrasound in the 1980s. The subsequent two-stage Seattle technique allowed for a planned homogenous distribution of radioactive sources throughout the gland resulting in biochemical control comparable to surgical and external beam radiotherapy series. With the advent of advanced computer software and improved imaging, the technique has developed accordingly to a single stage procedure with on-table dosimetric assessment. The principles of targeting dose to the prostate while avoiding surrounding organs at risk remain as relevant today as nearly a century ago. There is an array of techniques to consider for the novice PPB provider. Whether the evolution of PPB techniques will translate into improved biochemical control is yet to be seen.

Cerebral haemangiopericytoma treated with conservative surgery and radiotherapy.

Cerebral haemangiopericytomas are rare tumours that resemble meningiomas but behave more aggressively, with a tendency to metastasize. We report two patients with haemangiopericytoma who had limited surgical resections owing to perioperative blood loss but who had massive tumour shrinkage after a course of radical radiotherapy. We suggest a more conservative surgical approach to the management of these tumours.

The use of PET-18FDG imaging in the clinical evaluation of head and neck lymphoma.

Four patients with non-Hodgkin's lymphoma in the head and neck region were studied with positron emission tomography (PET), using the radioactive tracer 2-[F-18]-fluoro-2-deoxy-D-glucose (18FDG). This technique, which exploits the high metabolic rate of glucose in tumour tissue, enabled the extent of disease to be visualized. The localization of the tumour was improved by combining the data from the PET scan with those from CT scans or MRI. This technique (of PET-18FDG), using visual and semiquantitative analysis in the form of standardized uptake values, allowed the differentiation between reactive hyperplasia and nodal involvement with lymphoma. We believe that PET using the tracer 18FDG may play an important role in the evaluation of patients with head and neck lymphoma.

Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas.

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

Survival following interstitial brachytherapy for recurrent malignant glioma.

The treatment of recurrent malignant glioma is difficult and at present largely disappointing. Furthermore the results of any treatment modality need to be interpreted with knowledge regarding patient selection and timing of treatment. The results of interstitial brachytherapy using iodine-125 in 23 patients are presented. There were no operative complications. Median survival time from tumour recurrence and implantation was 36 and 25 weeks respectively. Karnofsky Performance Status (KPS) was significantly associated with survival, though patient age, original tumour histology, prior chemotherapy, and time to recurrence were not. Treatment does confer modest survival benefit as compared to controls, but our results are not as impressive as others. Reasons for this finding are discussed.

A pilot study using 99mTc to measure lead and platinum in the human kidney.

A pilot study has been conducted to investigate the hypothesis that the chemotherapeutic drug, cisplatinum, can mobilize skeletal lead. In vivo measurements of lead and platinum in the kidney of chemotherapy patients were performed with the technique of x-ray fluorescence, using 99mTc in a backscatter geometry. The results of the pilot study were inconclusive; the majority of patients exhibited no evidence of kidney lead at the level of system sensitivity, and negligible blood and urine lead levels.

Local control of T2/3 transitional cell carcinoma of bladder is correlated to differences in DNA supercoiling: evidence for two discrete tumor populations.

Single cell tumor suspensions were prepared from biopsy and urine samples from 48 patients with muscle invasive transitional cell carcinoma of the bladder. Prior to therapy, samples were irradiated in vitro with the condensation of DNA supercoils measured by the light scattered within a flow cytometer. Six months after completing a course of radiotherapy, the in vitro data were correlated with the presence or absence of local disease. After 12-Gy irradiation, nucleoid extraction and staining with 50 micrograms/ml ethidium bromide, 2 predominant forms of supercoiling behavior were seen. Nucleoids scattered either approximately 10% (Type I) or 35% (Type II) more light than unirradiated controls. Those patients with residual disease showed more Type I behavior (21 of 25; 84%) than those patients clear of disease (9 of 23; 39%) (P = 0.02). It is proposed that the ability of these tumor samples to adopt positive supercoiling after irradiation is related to a stronger association between individual DNA loops and their attachment to the nuclear matrix. This difference in nucleoid response within these tumor samples may be related both to intrinsic cellular radiosensitivity and, subsequently, to clinical radiocurability.

Stereotactic brachytherapy for malignant glioma using a relocatable frame.

Interstitial brachytherapy for recurrent gliomas normally necessitates the invasive application of a stereotactic frame by screw-fixation which must be kept on for several hours. The use of a relocatable stereotactic frame offers many advantages over conventional systems. We present our experience in 18 patients and verify that the frame used is accurate, comfortable, well tolerated and associated with no major disadvantages.

A correlation between nuclear supercoiling and the response of patients with bladder cancer to radiotherapy.

Single cell tumour suspensions were prepared from biopsy and urine samples from 28 patients with muscle invasive transitional cell carcinoma of the bladder. Nuclear extracts (nucleoids) containing intact chromatin were isolated from these cells and the condensation of DNA supercoils measured by the light scattered from individual nucleoids within a flow cytometer. Exposure of these nucleoids to 10 micrograms ml-1 ethidium bromide produced 78.9% increase in light scatter compared to those treated with 50 micrograms ml-1. This finding is consistent with the known effect of ethidium bromide on DNA supercoiling and confirms that the light scatter signal is responding to changes at this level of DNA organisation. Cell samples were also exposed to 12 Gy of gamma radiation and the effect on nucleoid light scatter recorded. Of the patients studied prior to radiotherapy, those with persistent disease 3 months after treatment generated an increase in nucleoid light scatter of + 9.35 +/- 4.8% after 12 Gy irradiation, of these, 2/14 produced nucleoids that relaxed by more than 10% compared to controls. Those patients with no evidence of disease after radiotherapy gave an increase in nucleoid light scatter after in vitro irradiation of + 19.3 +/- 4.5% of which 10/14 (71%) relaxed by more than 10%. It is proposed that the increased relaxation within the supercoiled DNA from patients whose tumours were undetectable 3 months after therapy, is related to the inherent radiosensitivity of these tumour cells. Such a difference in nucleoid response within tumour cells from patients that responded to radiation may arise due to a decreased affinity of DNA loops for the nuclear matrix. This structural change, at a site associated with the initiation of DNA synthesis, may affect the ability of cells to continue successful cell division after radiation damage.

Yttrium-87 for in vivo imaging.

Yttrium-87 with its daughter strontium-87m have been prepared in a form suitable for injection, and the biodistribution of 87Y-EDTMP determined in Balb/c mice. 87Y is suitable as a tracer for clinical investigations of 90Y.

Cellular radiosensitivity in V79 cells is linked to alterations in chromatin structure.

V79 cells grown as spheroids are more radioresistant than those grown as monolayers. Viable cells from spheroid culture contain restraints to ethidium bromide driven rewinding of DNA supercoils that are absent in monolayer cells. Spheroid cells also contain a DNA-protein matrix that is more resistant to detergent-induced degradation. The increase in structural integrity may be related to a 55-60 kD protein in the nucleoids of spheroid, but not monolayer cells. Spheroid cell radioresistance may therefore be related to a more stable chromatin platform for high fidelity repair of DNA damage.

The increase in radioresistance of Chinese hamster cells cultured as spheroids is correlated to changes in nuclear morphology.

Chinese hamster V79 cells grown as spheroids in roller culture are more radioresistant than those grown as monolayers. The supercoiled structure of chromatin, as salt-extracted nucleoids, has been examined using flow cytometry. Irradiated viable cells from spheroid culture contain restraints to supercoil relaxation that are absent in monolayer cells. Further analysis of the chromatin organization from each growth form shows that the radioresistant spheroid cells contain a DNA-protein matrix that is more resistant to detergent-induced degradation. The increase in structural integrity may be due to the retention of a 55-60 kDa protein that is apparent in the nucleoids of spheroid, but not monolayer cells. The increase in structural integrity of the spheroid cells may explain their greater radioresistance by providing a more stable platform for high-fidelity DNA damage repair.

Yttrium-90-EDTMP: a radiotherapeutic agent in the treatment of leukaemias.

Yttrium-90 chelated by the tetraphosphonate EDTMP achieved a high uptake in bone and a rapid clearance from all soft tissues compared with 90Y nitrilotriacetate, citrate and acetate. The biological half-life of 90Y in the bone was greater than 72 h, but the quantity, and therefore dose, could be reduced by 50% using repeated, non-toxic chelation therapy with the calcium salt of DTPA. This treatment should be able to supplement current treatments for leukaemia where the dose of external beam radiation is associated with considerable morbidity.

Glucose utilization in vivo by human pulmonary neoplasms.

Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission tomography (PET) we measured the rate of uptake of the glucose analogue 18fluoro-2-deoxy-D-glucose (18FDG) in 12 patients with carcinoma of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carcinoma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of 18FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scans over 1 hour. In each patient the rate of uptake of 18FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group the rate of uptake by the tumor was 211.4 +/- 69.4 ml/100 g/hr (mean +/- SD) compared to 31.9 +/- 13.2 in the contralateral lung (P less than 0.05). The tumor-to-normal tissue ratio of 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to brain tumors there was little correlation between tumor type and rate of 18FDG uptake. Measurements of glucose metabolism taken in vivo in human pulmonary tumors may lead to advances in screening, staging, and therapy.

Measurement of glucose utilisation with [18F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical methods.

A number of different analytical methods were applied to dynamic scans obtained with [18F]2-fluoro-2-deoxy-D-glucose and positron emission tomography. In particular, methods applying three, four, standard, or no rate constants were compared in four studies on three normal subjects. In addition, regional cerebral blood flow, oxygen utilisation, and blood volume were measured using the oxygen-15 steady-state inhalation technique. There was a large difference between values of glucose utilisation obtained with the various analytical methods, in particular between methods using three or four rate constants. This difference was not due to contamination of the tracer with [18F]2-fluoro-2-deoxy-D-mannose. For dynamic techniques, the separate measurement of regional cerebral blood volume was essential. Static techniques (single scans with standard or no rate constants) were best related to dynamic techniques utilising four rate constants. From the results, it followed, however, that these static techniques can only be applied clinically if relatively large disturbances of glucose metabolism and no changes in rate constants are anticipated. The lumped constant was assessed from the combined measurement of oxygen and glucose utilisation and was higher than previously reported.

Absence of irradiation induced ischaemic temporal lobe damage in patients with pituitary tumours.

This study was undertaken to confirm the belief that modern day external beam radiotherapy for patients with pituitary tumours should not be associated with any ischaemic temporal lobe damage. Using the oxygen-15 steady state inhalation technique and positron emission tomography regional temporal lobe blood flow, oxygen extraction fraction and oxygen utilisation were measured in 10 normal volunteers and 11 patients with pituitary tumours treated by irradiation. The patients were studied between 1 and 10.9 years after radiotherapy. We found that temporal lobe oxygen utilisation in the irradiated group (mean 2.11 +/- 0.23 ml of O2/100 ml tissue/min) did not differ from the normal group (mean 2.13 +/- 0.26 ml of O2/100 ml tissue/min). This suggests that total doses of between 35 and 56 Gy, delivered in fractions of less than 2 Gy, can be given to a pituitary tumour without demonstrable damage to normal temporal lobe.

Studies on regional cerebral pH in patients with cerebral tumours using continuous inhalation of 11CO2 and positron emission tomography.

Regional cerebral pH (rpH) was measured in 12 patients with cerebral tumours and in 5 normal subjects using continuous inhalation of 11CO2 and positron emission tomography (PET). Cerebral tumours with a disrupted blood-brain barrier (BBB) on computed tomography scanning had a similar rpH to that of equivalent regions of contralateral brain tissue (mean tumour rpH, 6.98; mean contralateral brain pH, 6.99). Cerebral tumours with an intact BBB were consistently found to be more alkaline than contralateral brain tissue (mean tumour rpH, 7.09). There was no significant difference between the mean rpH values obtained for peripheral cortical gray and central white matter in normal subjects (7.02 and 6.98, respectively). It is concluded that in spite of reports of raised levels of aerobic glycolysis in neoplastic tissue, there is no evidence that cerebral tumour rpH values are depressed.

Studies on cerebral oxygen metabolism, blood flow, and blood volume, in patients with hydrocephalus before and after surgical decompression, using positron emission tomography.

Cortical oxygen utilization, oxygen extraction, blood flow, and blood volume, have been measured in patients with hydrocephalus before and after surgical decompression using positron emission tomography (PET). The hydrocephalus subjects fell into two categories: patients with recent-onset obstructive hydrocephalus and symptoms of raised intracranial pressure due to obstruction of cerebrospinal fluid (CSF) drainage by posterior fossa or third ventricular cerebral tumours, and patients with hydrocephalus of more insidious onset that was associated either with congenital abnormalities, or which was idiopathic. The hydrocephalus subjects had a significantly reduced level of mean cortical oxygen utilization (rCMRO2) and mean cortical blood flow (rCBF) compared with age-matched normal controls. Patients with recent-onset obstructive hydrocephalus associated with cerebral neoplasia had inappropriately low levels of cortical blood flow compared with their levels of cortical oxygen utilization, all having elevated levels of cortical oxygen extraction (rOER). Levels of cortical blood flow in the group of patients with more insidious-onset hydrocephalus matched levels of cortical rCMRO2, all these subjects having normal levels of rOER. All those hydrocephalus subjects who had a raised cortical oxygen extraction preoperatively increased their cortical blood flow following cerebral decompression. No improvement, however, was noted in their mean cortical oxygen utilization. By contrast, those hydrocephalus subjects with normal baseline levels of cortical extraction showed no improvement in mean cortical blood flow, oxygen utilization, or cognitive function after surgical intervention. It is concluded that if cortical oxygen extraction is elevated, hydrocephalic patients are likely to improve their cortical blood flow following cerebral decompression.