Positron emission tomography: A new investigational area for cancer research

Clinical Oncology (1996) 8:7-14 © 1996 The Royal College of Radiologists

Clinical Oncology

Review Article Positron Emission Tomography: A New Investigational Area for Cancer Research P. W e l l s , R . J. A . H a r t e a n d P. P r i c e Royal Postgraduate Medical School, Hammersmith Hospital, London, UK

INTRODUCTION Recent advances in molecular biology have provided valuable insights into the mechanisms of cell cycle control and genetic susceptibility to carcinoma that may be exploited, providing us with future targets for therapy. Despite these laboratory developments there have not been improvements in our clinical methods of assessment of treatment effects in tumours. Positron emission tomography (PET) in oncology is now emerging as a valuable functional imaging tool, providing us with unique in vivo physiological and pharmacokinetic data, which will facilitate the effective translation of laboratory developments into clinical practice.

BACKGROUND Fig. 1. Diagrammatic illustration of coincidence detection using PET.

Principles of PET Positron emission tomography (PET) is a non-invasive imaging technique, which allows the study of tissue function and provides insights into tumour biology, metabolism the drug pharmacokinetics in vivo. PET utilizes proton rich radionuclides, which decay by positron emission. Once emitted from the parent nucleus, the positron collides with an electron in the surrounding tissue after travelling a short distance. This results in the annihilation of the positron/electron pair and the production of two 511 keV photons emitted at approximately 180° to each other (Fig. 1). These photons are recorded by two opposing coincidence detectors, which transmit a signal if both are stimulated simultaneously. No physical collimation is required to define the path of the photons, which is the feature responsible for the favourable increase in sensitivity of this method when compared with other radionuclide imaging techniques (e.g. single photon emission computed tomography (SPECT). By placing coincidence detecCorrespondence and offprint requests to: P. Wells, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.

tors around the body, sufficient angular information can be obtained to allow accurate complete reconstruction of the regional tissue concentrations of tracer. Modern PET cameras are able to measure radioactivity concentration with a spatial resolution of approximately 5 mm (full width half maximum). The counts are collected over predetermined time intervals and the information for each plane of interest is binned into time frames, providing accurate temporal information and allowing the demonstration of tracer pharmacodynamics over a section of the body, spanning 10 cm in the axial direction. During each study a transmission scan is performed to allow correction for tissue density to be made. This is subsequently used to provide a quantitative measure of tracer concentration.

RADIOCHEMISTRY Tracers are labelled with positron emitting nuclides of the common biological elements (such as oxygen, carbon, nitrogen and hydrogen), by substitution of the stable nuclide with the positron emitting form.

P. Wells et al.

8 Table 1. The common radionuclides used in oncology Radionuclide

Half-life

1502

2 min

C1502, H2150 1so 2 C150 11C 1IC methionine 11C glucose nC drugs nC raclopride 11C somatostatin ~1C thymidine lSF

Used to measure

Blood flow Oxygen metabolism Blood volume 20 rain Amino acid uptake Glucose utilization Drug uptake (e.g. carmustine) Dopamine receptor Somatostatin receptor Proliferation 110 rain

lSF deoxyglucose lSF deoxyuridiue lSF fluorouracil lSF misonidazole mF oestradiol

Glucose utilization Pyrimidine uptake Drug uptake Hypoxiccell sensitizers Oestrogen receptors in breast

6SGa 6SGa EDTA 13N2 13NH3

68 min

1241

4 days

APPLICATIONS

Blood-brain barrier 10 rain Blood flow Monocolonal antibodies Iodine therapy dosimetry

This ensures that their biological and chemical properties are identical to the unlabelled compound and that the biological path of interest remains unperturbed. Initial PET studies in oncology were dictated by a limited number of available tracers. Physiological mechanisms, such as tumour blood flow using infused H2150 or inhalation of C1502 were demonstrated, or glucose metabolism using fluoro-2deoxyglucose (FDG). Developments in radiochemistry have produced a vast array of tracers, allowing expansion of the physiological and pharmacological processes that we are now able to follow (Table 1.)

Tracer Models Accurate tomographs already exist from which data is extracted for defined areas of interest, but, in order to quantify these physiological and pharmacokinetic parameters derived from the data, accurate tracer models are also required. For instance, the signal recorded of the tracers does not provide chemical resolution if the tracer is metabolized in vivo. Mathematical modelling may enable chemical resolution and accurate quantification of biological processes to be achieved. To ensure correct interpretation of scan data it is important that models used are validated. When applying a model to oncological scan data one assumes: The model is an oversimplification of the real biological situation, representing the key dynamics only. A model validated for normal tissue often requires different underlying assumptions when applied to pathological conditions. The possibility of breakdown of the model increases as the complexity of the pathway under consideration increases.

The first account of positron imaging with single probes in coincidence dealt with the localization of brain tumours [1,2]. Subsequent developments resulted in the first whole body tomograph specifically designed for human studies [3,4]. Initial research centred around neurological applications, reflected by the first reported studies in oncology using the same techniques, concentrating on the measurement of blood flow, oxygen and glucose utilization, and blood volume in cerebral tumours. These early studies were restricted by the small number of available tracers, which may have led to PET in oncology being limited to a radiological imaging tool, with little functional information available. However, recent development in radiopharmaceutical labelling have broadened the repertoire, which now extends to demonstration of drug pharmacokinetics following administration of tracer doses of the parent drug. This provides us with unique insights into drug distribution and efficacy in vivo, allowing the technique to be developed to answer specific clinical and scientific questions.

Tumour Physiology Tumour Perfusion, Blood Flow and Hypoxia Quantitative tumour PET studies originally concentrated on measurement of blood flow, blood volume and oxygen utilization in brain tumour by the oxygen-15-steady state equilibrium technique [5-7], which was the technique developed for normal brain. By this method, three separate emission studies are performed. The first and second during continuous inhalation of tracer amounts of oxygen-15 labelled CO2 and molecular oxygen respectively, and the third after inhalation of tracer amounts of carbon-ll labelled CO. The measurement of regional blood flow (rBF) and regional blood volume (rBV) may be carried out. The former represents capillary flow (tissue perfusion), but, since the technique is dependent on tissue exchange of labelled water, which does not account for shunted blood, the rBF therefore reflects oxygen delivery to the tissues [8]. The latter (rBV) reflects tissue vascularity (i.e. the volume of vessels within a region). Following the use of these initial flow studies, the measurement of fractional extraction of oxygen (rOER) and utilization (rMRO2) was improved [7, 9], and the relevance of the technique to tumour pathology defined by simulation studies [10]. A number of consistent observations regarding brain tumours can be drawn from this work. Tumours demonstrate variability of perfusion and a high degree of tumour vascularity, with no relationship between these parameters [11]. Although the technique would be expected to underestimate the rOER in tissue, a consistent reduction in the average percentage of oxygen delivered by arterial blood and consumed by tissue relative to surrounding and

Positron Emission Tomography in Cancer Research

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normal brain (i.e. rOER) was found. This phenomenon extended to oedematous white matter and neighbouring brain tumours, indicating that the decrease is not a local phenomenon [11] (Fig. 2). The relationship between tumour and contralateral brain rOER is represented in Fig. 3. The points above the line represent increasing tumour rOER in contrast to the contralateral hemisphere, where all points are below NORMAL

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Table 2. Summary of tumour blood flow studies Oxygen supply is sufficient to fulfil the metabolic demands of the bulk of the tumour tissue. There is no indication of local isehaemia in oedematous brain tissue. There is a loss of haemodynamie reserve in the brain of patients with cerebral tumours. Cortex overlying oedema is metabolically depressed but not ischaemic. Perfusion of non-nec-rotic breast tumours is higher than normal breast tissue.

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Fig. 2. Summary of oxygen extraction fraction (OER) data.

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Fig. 3. Comparison of contralateral (C/L) r O E R with (left) tumour and (right) oedematous white matter rOER.

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Fig. 4. Summary of oxygen utilization data.

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the line, representing a low oxygen extraction for tumour and inferring that oxygen supply (blood flow) is sufficient to fulfil the metabolic demand of the tumour for oxygen. Figures 4 and 5 indicate the relationships between rMROz (= CMRO2 in Fig. 4) and rBF (-- CBF in Fig. 5). They show that utilization is always low despite a variable blood flow and it would seem that macroscopically at least these tumours appear to be in a state of 'luxury perfusion' (i.e. there is adequate oxygenation and perfusion for the metabolic demand of the tumour, even when rBF is low) [9]. PET does not, however, account for the microenvironments within a tumour, which are hypoxic and extracting available oxygen maximally. The steady state technique was modified for breast tumours, where blood flow was found to be variable and substantially higher than in normal breast [12]. In contrast to the situation in brain tumours, the rMRO2 was higher in tumorous than in normal breast, but, in common with cerebral tumours a low oxygen extraction prevailed. This discrepancy in blood flow between tumours and normal breast has recently been confirmed using the more accurate dynamic 150-labelled water technique [13], which involves continuous infusion of C1502 via a face mask. In the lungs, the 1SO label is rapidly transferred to the pulmonary water pool by carbonic anhydrase. This technique has the advantage of greater accuracy in determination of flow without loss of spatial resolution. Also, flow and volume of distribution (estimate of tissue being perfused) are measured simultaneously and it is less sensitive to the tumour's heterogeneity. (Conclusions of the above studies are represented in Table 2.)

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Fig. 5. Summary of perfusion data.

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18F-fluoro-2-deoxy-D-glucose (FDG) has now become established as the most common oncological PET imaging technique. This methodology was based on Warburg's biochemical observations [14,15] that malignant transformation in cells is associated with a high glycolytic rate. The mechanisms underlying this phenomenon are not fully understood. However, it is known that the neoplastic transformation of some cell lines occurs in conjunction with increased membrane glucose transport capability [16] and that tumour growth rate is linked to the magnitude of increase in glycolysis [17]. FDG competes for the same transport and metabolic pathways as glucose, but, once in the cell, it cannot be catabolized further and becomes metabolically

10 trapped, accumulating in tissue at a rate proportional to glucose utilization. FDG PET investigations of brain tumours provided the impetus for the application of PET to other organ systems. DiChiro et al. established and developed FDG PET imaging of astrocytomas as a method of grading and assessing recurrence and prognosis, and as a surrogate measure of tumour response to therapy [18-22]. Outside the CNS, squamous cell carcinomas, primarily of the head and neck, have high glycolytic rates, which makes these lesions amenable to FDG PET imaging. Patients with tumour cells having an abnormal D N A content (aneuploidy) generally have a higher proportion of cells in S phase and a less favourable prognosis than those with a normal D N A complement. Reports suggest a good correlation between proliferative activity and FDG uptake in vivo [23-25] (although their results are not universal [26]), and a variable relationship with tumour grade. Minn et al. did not find a correlation with histological grade and FDG uptake in head and neck tumours [27] (unlike astrocytomas), indicating that the relationship between glucose uptake, level of differentiation, and D N A ploidy may depend on the tumour tissue of origin. Recent studies with FDG PET in breast cancer have demonstrated the potential of the method to detect primary and metastatic disease [28,29]. Preliminary results have suggested that serial quantitative imaging may permit assessment of tumour responsiveness during treatment [30] and that its diagnostic accuracy compares very favourably with other imaging techniques [28,29]. Recently, concerns have been voiced regarding the modelling of lSFDG in gliomas and the variability and applicability of analytical techniques to a variety of tumours [31-34]. Despite these caveats, FDG PET successfully distinguishes tumour from radiation necrosis and normal or fibrous tissue. The less clear relationship between FDG uptake and proliferative rate is thought to be related to FDG uptake in nontumorous cells, such as macrophages, which infiltrate marginal areas of necrosis as well as newly formed granulation tissue around tumour, particularly following treatment [35,36]. The ability of FDG PET to assess the outcome of therapy may be of most use early in drug development, in parallel with Phase I and Phase II drug trials. For example in a UK Cancer Research Campaign Phase II study, the response to temozolomide in brain tumours has been related to changes in tumours glucose metabolism. Such changes, 7 days after the first course of therapy, predicted for clinical outcome; the greatest reduction in metabolism corresponded to the best response [37]. This work will be extended to quantify in vivo the effects of dose scheduling and the addition of radiotherapy.

Tumour Proliferation Recently, 2-nC thymidine has been developed as a potential in vivo measure of cell proliferation. Data from normal tissue models have shown correlations between 2 - n c thymidine uptake (as determined by PET), D N A incorporation in regenerating and non-

P. Wells et al. regenerating livers, and cell proliferation [38,39]. Clinically, the method was first evaluated in patients with lymphoma, using thymidine labelled in the methyl position. PET-detected activity was found to correlate with histological grade of tumour [40]; this has been mirrored by murine models [41]. Thymidine labelled in the 2-C position produces PET images superior to those obtained with 11C methyl thymidine as a result of the fewer labelled metabolic products, 11CO2being the major metabolite in tissue and in blood. 2-nC thymidine may be a more specific marker of the antiproliferative effect of anticancer therapy. Past studies have demonstrated a change in cell proliferation following radiotherapy [42,43], but further work is required to assess the magnitude and timing of such changes during treatment with differing fractionation schedules. This work will be extended to the assessment of antiproliferative effect, demonstration of the metabolic pathway of thymidine, quantification of enzyme inhibition (e.g. thymidylate synthase), and the response of tumours to chemotherapeutic agents, thus providing information that may be used in the individualization of patients' treatment regimens.

Tissue/Tumour Pharmacokinetics PET is an in vivo tracer technique, which allows quantitative, sensitive and specific assessment of molecular pathways and mechanisms. It provides quantitative information on the concentration of tracer in tissue and its pharmacokinetics. This information is then used to make inferences about a biochemical pathway or physiological attribute of the tissue of interest, but interpretation of such data is limited by the constraints of the mathematical models used. Drug pharmacokinetic studies have attractions and limitations as a consequence of the physical and biochemical characteristics of the positron emitting labels. The main advantage is that the substitution of the stable nuclide with the positron emitting form affects neither the chemical nor the biological properties of the molecule. The high specific activity of the labelled molecules, coupled with the sensitivity of the PET camera, allows picomolar concentrations of tracer to be measured. The recent development of techniques that have allowed the radiolabelling of chemotherapeutic agents, has resulted in tracer doses of drug now being administered. This provides pharmacokinetic information with minimal toxicity to the patient. This characteristic may be utilized in the assessment of anticancer drugs early in Phase I studies, which provides unique insights into drug pharmacokinetics, rather than having to rely on extrapolation from plasma data. The main limitation of the technique as a pharmacokinetic tool is its lack of chemical resolution (i.e. an inability to distinguish between parent drug and its metabolites). This function may be achieved by the complementary use of NMR spectroscopy, which provides the investigator with molecule specific images whose drug and catabolite concentrations mirror those estimated for tissues in the patient scanned. Alternatively, sequen-

Positron Emission Tomography in Cancer Research

tial studies using radiolabelled metabolites may be used to allow correction to be made for the contribution of metabolites/parent tracer to the signal. PET provides an advantage of several orders of magnitude in sensitivity over NMR, with high temporal and spatial resolution. This, with its tissue specific kinetic information, can provide unique spatial and molecular information for in vivo drug monitoring in animals and humans. The following examples illustrate how far the field of study in labelled anticancer drugs has progressed. The most widely investigated group of drugs are the fluoropyrimidines, 5 FU and fluoro-deoxyuridine (FUdR). 5-1sFU studies have focused on turnout drug and metabolite levels as predictors of chemotherapy response, with promising results [44,45]. Knowledge of the metabolic activation and elimination of 5-FU allowed an evaluation of the utility of established PET methodology and an appraisal of new approaches to tracer concentration normalization in these studies. Tumour heterogeneity may preclude tracer uptake prediction from 5-1sFU plasma pharmacokinetics in the tracer only studies. However, the suggestion of an association between drug delivery (tumour blood flow) and turnout drug exposure (represented by the area under the turnout radioactivity versus time curve - AUC) encourages further investigation. Poor drug access may be an obvious explanation for lack of drug activity. PET studies have demonstrated different kinetic behaviour between bolus and continuous i.v. infusion of 5-FU. The relationship between plasma 5-18FU AUC and normal tissue tracer AUC values has been demonstrated, suggesting that plasma levels can predict normal tissue uptake. This relationship has not been confirmed for turnout, which may indicate that plasma pharmacokinetic measurements alone are insufficient to predict tumour uptake [46]. This technique also allows the assessment of the effect of blood flow modulators and biochemical modulators (e.g. N-phosphonacetyl-Laspartate (PALA)) on turnout drug delivery, the PET data having suggested a mean increase in the tumour uptake of 5-FU following administration of PALA. Tracer kinetic studies defining tumour and normal tissue pharmacokinetic data may confer advantages in developing adaptive dosing strategies. Tumour pharmacokinetic evaluation may be central in the successful translation of novel anticancer therapies from the laboratory to the clinic. The following serve as examples. DACA (N-[2-(dimethylamino)ethyl]-acridine-4carboxamide) is an anticancer agent developed at the University of Auckland, New Zealand, in a synthesis and testing programme for antitumour tricyclic carboxamide-based DNA intercalating agents [47]. A series of DACA PET studies in volunteer cancer patients was completed in advance of the Phase I trial, which is now in progress. This provided preliminary information on biodistribution and metabolism in humans, and a further series of studies is being undertaken in parallel with the Phase I trial. The significance of the pre-Phase I studies rests in the ability to assess spontaneous human tumours in vivo, bypassing the problems of relevance of in vitro models and species specificity with animal models,

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although caution is still required when extrapolating from tracer to pharmacological doses. Temozolomide is an oral cytotoxic prodrug, which, under physiological conditions, undergoes ring opening to the DNA-methylating triazine 5-(3-methyltriazen-l-yl) imidazole-4-carboxamide (MTIC). This binds to DNA bases, resulting in methyl addition products. The O6-methylguanine formed appears to be the major cytotoxic species [48]. The methyl addition products are inactivated by O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein. Animal studies have demonstrated a good tissue distribution profile with penetration into the brain, while Phase I studies have demonstrated excellent oral bioavailability in humans. Temozolomide has been radiolabelled with carbon-ll, thus allowing direct in vivo investigation of the molecular pharmacology of the drug following of tracer doses. Human in vivo biodistribution is obtainable using a multiorgan counter, while tumour and normal tissue uptake studies have been undertaken in patients with high grade gliomas.

FUTURE DEVELOPMENTS Recent developments in the PET technique have allowed us to capitalize on leads provided for us by the drug development agencies. Present projects concentrate on the demonstration of drug activity in tumours and normal tissues in vivo, where activity has been already demonstrated. In the future, this will be extended to investigating drugs with promising new mechanisms of action, providing an insight into drug toxicities and efficacy on the basis of drug concentrations in the tissue following administration of tracer doses and thus limiting toxicity to the patient. Table 3 represents possible future developments of the technique, with the most recent developments outlined in greater detail below.

Mechanisms of Drug Action Thymidylate synthase (TS) inhibitors are classical antifolates. They possess a para-amino benzoyl glutamate moiety, which makes them substrates for the folyl-polyglutamate synthase enzyme. By the action of this enzyme, they are converted to intracellular polyglutamates, which increase drug potency by causing intracellular retention and increasing the inhibitory effect on thymidylate synthase. AG337 binds to the thymidylate synthase enzyme, which would usually result in influx of extracellular thymidine into the cell; these cell lines are unable to overcome this blockade and thus die. Direct insights into the in vivo mechanism of action of inhibitors of TS in turnouts and normal tissue may be investigated by quantification of tumour thymidine salvage using 2- 11C thymidine. If TS inhibition does occur following administration of the drug, then pathways of thymidine salvage should be activated, which, it is anticipated, would result in an increase in

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P. Wells et al.

Table 3. Future developments in PET in oncology

Project

Ligand

Aim

Investigation of prodrug targeting ADEPT prodrug GPAT

[18F]-fluorocytosine

To quantify prodrug targeting To assess efficacy of gene transfer systems

Mechanism of action of anticancer compounds [11C-N-methyl]temozolomide [I1C-N-carbonyl]temozolomide 2-[11C]thymidine

To demonstrate alkylation in vivo To quantify ring opening To demonstrate mechanism of action of the thymidylate synthase inhibitor AG337 To quantify TS inhibition in vivo

[11C]patrin or [11C]benzylguanine

To quantify the DNA repair protein 0 6methylguanine-DNA methyl transferase (MGMT) in vivo To confirm and quantify in vivo effects of multidrug resistance

Investigation of mechanisms of resistance to anticancer therpay

[11C]adriamycin

thymidine uptake from the plasma and extracellular thymidine pool. Changes in injected 2-11C thymidine uptake into tumour and normal tissue may parallel this effect and be quantifiable by PET providing a degree of TS inhibition, thus substantiating the mode of action in neoplastic tissue. This information could be used to provide a guide to the optimal dosing strategy that may be achieved before reaching the maximal tolerated dose. This would speed the introduction of effective drugs into clinical practice. The antitumour activity of temozolomide is largely attributable to its ability to methylate DNA, which occurs by the formation of the reactive methylating species, MTIC. By radiolabelling temozolomide in certain positions, demonstration of the metabolic pathway in vivo may be possible. By the incorporation of C into temozolomide at the 3-N-methyl position, it should be possible to demonstrate alkylation in vivo. Conversely, preparation of labelled temozolomide with l t c in the 4-carbonyl position would not be expected to incorporate the label into DNA; following ring opening, it would result in the production of ~C labelled CO2. This is ultimately expired and is thus quantifiable. By this differential labelling technique it is hoped that quantification of the ring opening in individual patients can be achieved, with confirmation of the drug's mechanism of action in vivo.

Molecular pharmacology The cytotoxicity of temozolomide in vitro has been found to correlate with methylation of DNA at the 0 6 position of guanine. The clinical utility of temozolomide may therefore be limited by the repair 6 protein, MGMT, which repairs O-alkylguanine adducts. Preclinical investigation suggests that this resistance may be circumvented by preadministration of O6-benzylguanine (O6BG), a potent inhibitor of MGMT. Thus, significant potentiation of temozolomide may be achievable through modulation of MGMT levels with O 6BG. The O 6-alkyl-

guanine adducts represent a relatively minor proportion of all temozolomide DNA methylation. Preliminary in vitro work will ascertain whether an increase in 11C-temozolomide labelled in the 3-Nmethyl position is quantifiable following depletion of MGMT with O6-BG and temozolomide itself. This technique could then be exploited in vivo in order to correlate enhanced DNA methylation with tumour response. The mechanism may be studied directly by labelling O6-BG with carbon-11. Depletion of the DNA repair protein is rapid, and will allow quantitative assay of O6-MGMT levels in vivo. Such information will be useful in the optimization of dose schedules by defining the relationship between temozolomide treatment and the level of protein depletion in vivo.

CONCLUSIONS Although PET techniques have been refined for a variety of normal tissues, the technique, when applied to oncology, is still in its infancy. For its full potential to be realized, close collaboration is required between drug developers and clinicians, particularly with regard to its use in the early stages of drug assessment. Methodological developments will hopefully extend its application to the investigation of mechanisms of drug action and confirmation of drug targeting and efficiency. Techniques such as PET, which allow the evaluation of tumour drug kinetics and the effects of therapy on tumour proliferation, physiology and biochemistry, are likely to become of increasing importance in the successful transition of new anticancer therapies from the laboratory to the clinic.

Acknowledgements. This work is funded by grants from the Medical Research Council, Cancer Research Campaign and Schering Plough, UK. The work carried out in connection with AG337 has been in collaboration with Professor Newell and the Cancer Research Campaign, Phase I study.

Positron Emission Tomography in Cancer Research

The work carried out in connection with acridine carboxamide has been in collaboration with Professor Baguley and Professor Denny, and the Cancer Research Campaign Phase I study. The work carried out in connection with temozolomide has been in collaboration with Professor Newlands, Charing Cross Hospital, London, UK and the Cancer Research Campaign Phase I and Phase II studies. Figures 2-5 have been reprinted from Cancer Metastasis Rev 1987;6:521-39 [11], by kind permission of Kluwer Academic Publishers.

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Clinical Trials in Oncology EDITOR'S NOTE Clinical Oncology is k e e n to s u p p o r t g o o d clinical trials in o n c o l o g y a n d to f u r t h e r this o b j e c t i v e w e a r e n o w i n c l u d i n g in t h e j o u r n a l s u m m a r i e s of a n u m b e r o f studies which a r e actively r e c r u i t i n g at t h e p r e s e n t t i m e . T h e s e all i n c l u d e c o n t a c t a d d r e s s e s for r e a d e r s w h o m i g h t b e i n t e r e s t e d in p a r t i c i p a t i n g in t h e s e studies. W e a r e v e r y h a p p y to r e c e i v e n o t i c e s a b o u t n e w trials o r d e t a i l s of existing studies s e e k i n g to i n c r e a s e r e c r u i t m e n t . Such n o t i c e s s h o u l d follow t h e f o r m a t o f t h o s e in this issue a n d b e s e n t to t h e Editor.

LY05: A R A N D O M I Z E D TRIAL OF R A D I O T H E R A P Y A L O N E VERSUS 3 CYCLES OF CHOP C H E M O T H E R A P Y PLUS R A D I O T H E R A P Y VERSUS 6 CYCLES OF CHOP C H E M O T H E R A P Y PLUS R A D I O T H E R A P Y FOR E A R L Y STAGE AGGRESSIVE N O N - H O D G K I N ' S LYMPHOMA Clinicians may randomise between all 3 arms or between any 2 of the arms on an individual patient basis, by choosing one of the following randomisation options.

• All 3 treatments • Radiotherapy v CHOP x 3 + radiotherapy • Radiotherapy v C H O P x 6 + radiotherapy • CHOP x 3 + radiotherapy v CHOP x 6 + radiotherapy

Inclusion Criteria: • Biospy proven N H L of intermediate or high grade histology (excluding lymphoblastic and diffuse small non-cleaved Burkitt's or non-Burkitt's type) lymphomas arising in nodal or extra nodal sites. • W H O performance status 0, 1 or 2. • Greater than 15 years of age. • Stage I, IE, II, IIE, except bulky (>10 cm) abdominal presentation. • Informed consent.

Exclusion Criteria: • Testicular, brain gastrointestinal and skin primaries. • B Symptoms. • Patients in whom doxorubicin may be contra-indicated (eg. those with history of cardiac failure or with cardiomegaly on chest X-ray). • Previous chemotherapy or radiotherapy. • Previous malignancy, except basal cell carcinoma of the skin or cervical carcinoma stage I. • Known to be HIV positive.

Clinical Coordinators: Alan Horwich, Department of Radiotherapy Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: 0181 642 6011; Fax: 0181 643 8809. Ben Mead, CRC Medical Oncology Unit, Royal South Hants Hospital, Graham Road, Southampton SO9 4PE, UK. Tel: 01703 634288; Fax: 01703 825441.

To receive a copy of the protocol please contact: Della Gibson, MRC Cancer Trials Office, 5 Shaftesbury Road, Cambridge, CB2 2BW, UK. Tel: 01223 311110; Fax: 01223 311844.

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