Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide

M. Brada1,2,*, S. Ashley4, A. Dowe2, A. Gonsalves2, A. Huchet2, G. Pesce2,{dagger}, M. Reni5, F. Saran2, B. Wharram2, M. Wilkins6 and P. Wilkins3

1 Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research, London; 2 Neuro-Oncology Unit, The Royal Marsden NHS Trust, Sutton, Surrey; 3 Department of Neuropathology, Atkinson Morley Wing, St George's Hospital, London; 4 Computing Department, The Royal Marsden NHS Trust, Sutton, Surrey, UK; 5 S Raffaele Scientific Institute, Servizio di Radiochemoterapia, Milan, Italy; 6 Department of Oncology, Royal Sussex County Hospital, Brighton, UK

* Correspondence to: Prof. M. Brada, The Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8661-3272; Fax: +44-20-8661-3127; Email: michael.brada{at}icr.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
Background:: The aim of this study was to assess the efficacy of new agents in patients with malignant glioma in a neoadjuvant setting not confounded by surgery. The first study of neoadjuvant temozolomide aimed to provide a benchmark for future evaluation of new treatments.

Patients and methods:: This was a multicentre phase II study of chemotherapy in patients with histologically verified glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) who had undergone biopsy alone. Patients were planned to receive two cycles of temozolomide at 200 mg/m2 orally daily for 5 days at a 28-day interval prior to radiotherapy. Response was assessed by two central observers on pre- and post-chemotherapy enhanced scans using bi-dimensional criteria and as progression-free survival (PFS) at the time of second assessment prior to radiotherapy. Withdrawal from the study due to worsening clinical condition was, in the absence of second imaging, assessed as progressive disease. Survival and quality of life (QOL) were secondary endpoints.

Results:: Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study and 187 were analysed. Overall, 162 patients were assessable for response; seven had partial and 25 had minimal response. The objective response rate was 20% [95% confidence interval (CI) 14–26%] and PFS prior to commencing radiotherapy was 64% (95% CI 57–72%). The median survival was 10 months, and 1-year survival 41%. The median survival of responders was 16 months compared to 3 months in patients with progressive disease (P <0.001 on multivariate analysis).

Conclusion:: The phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide provide a benchmark for assessment of efficacy of other agents and combinations.

Key words: temozolomide, malignant glioma, new agents


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
Despite intensive treatment with surgery, radiotherapy and chemotherapy, the median survival of patients with malignant glioma remains in the region of 9–12 months. Many systemic agents have been explored in the treatment of high-grade glioma with the aim of improving outcome. They were usually administered at the time of recurrence and following promising evidence of activity, some were assessed in an adjuvant setting. Of the various chemotherapeutic agents tested, nitrosoureas are currently considered the most effective with a reported response rate of between 10 and 40% [1Go, 2Go]. When administered in an adjuvant setting following the completion of radiotherapy, their benefit in terms of survival is small [3Go, 4Go], and in some studies, non-existent [5Go].

A number of new systemic agents have been introduced with apparent activity in patients with recurrent high-grade gliomas including conventional cytotoxic agents [6Go, 7Go], agents altering blood–brain barrier properties [8Go], antiangiogenic agents [9Go, 10Go] and others. Despite the belief in the superiority of some new agents [11Go], the best alternative to nitrosoureas, either as single agent or a combination, have not been defined as there are no robust comparative studies available. Introduction of such chemotherapy into an adjuvant setting is therefore speculative and, without clearer data on true efficacy, leads to frequent disappointment with negative randomised trials.

It would be useful to classify new agents into broad categories of efficacy prior to their introduction into costly and manpower intensive phase III studies. Conventional phase II design at the time of recurrence has been used for this purpose with largely disappointing results as no agent or combination have been identified which demonstrate clear survival benefit in an adjuvant setting. Testing of new agents and combinations in recurrent setting is fraught with difficulty because of a variety of confounding factors [12Go, 13Go]. Contrast enhancement on computed tomography (CT) and magnetic resonance imaging (MRI), while not a true representation of tumour size as it demonstrates the region of blood–brain barrier disruption, is accepted as a surrogate for tumour size. As the size of region of enhancement is altered by surgery, radiotherapy, and by the use of steroids, it is an unreliable measure in heavily pre-treated patients with recurrent disease [13Go]. To overcome the problem of imaging assessment in recurrent setting, the endpoints of survival and progression-free survival (PFS) at a specific timepoint have been employed [14Go, 15Go]. The PFS endpoint offers a reasonable alternative although it requires intensive imaging and follow-up. The survival endpoint is confounded by the use of other treatments after failure of the therapy under test.

New agents have also been employed prior to definitive treatment with radiotherapy. Neoadjuvant studies with carmustine (BCNU) and cisplatin have demonstrated a relatively high response rate and the short delay to irradiation has been without detriment in terms of survival [16Go, 17Go]. While it is not clear whether the relatively high response rate noted in this setting is of ultimate survival benefit when tested in an adjuvant setting, these types of studies provide a new benchmark for comparison of different treatment regimens. This neoadjuvant study design, although not confounded by previous therapy is also not without problems. Many patients have surgery which, for most, is an attempt at partial or radical tumour excision. While the confounding effect of surgery on the assessment of tumour size is reduced by early postoperative scanning, the interpretation of changes remains difficult without clearly defined meaning. The neoadjuvant chemotherapy study design employed, although similar to that pioneered by the NCI Brain Tumour Consortia [16Go], has an important difference. Patients included in the study had biopsy alone with no other surgical interference and chemotherapy was limited to two cycles.

Temozolomide came to clinical testing in the early 1990s [18Go] and has been licensed for use in recurrent malignant glioma since 1999. Phase II studies tested the activity of temozolomide in patients with recurrent malignant glioma [14Go, 15Go, 19Go], as adjuvant and concomitant therapy [20Go] and in a neoadjuvant setting [21Go]. Nonetheless, the effectiveness in patients with primary high grade glioma prior to definitive radiotherapy remains to be defined.

We report the results of a large multicentre neoadjuvant phase II study to determine the efficacy of temozolomide in patients with primary anaplastic astrocytoma (AA) and glioblastoma prior to the use of radiotherapy following minimal surgical resection. The aim of the new study design is to find a potentially effective therapy which could be brought into randomised trials of adjuvant therapy with reasonable confidence of a positive result. The aim of this first study of conventional administration of temozolomide was to serve as a benchmark for the future evaluation of alternative regimens which would allow separation of new treatments into broad efficacy bands.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
The efficacy of temozolomide was assessed in patients with primary high grade glioma following limited surgery, prior to radiotherapy, in a multicentre, phase II study. The primary endpoint was objective response rate on imaging, not confounded by surgery and radiotherapy, with survival as a secondary endpoint, measured from the date of entry into the trial.

Patients with histologically verified glioblastoma multiforme (GBM), gliosarcoma (GS) and AA, who had undergone either biopsy alone or limited surgery not interfering with the assessment of tumour size and were planned to receive radical radiotherapy were recruited from UK and European centres. Tumour histology was reviewed centrally by a neuropathologist (P.W.) and was classified as GBM, AA, GS and high grade glioma not otherwise specified (HG NOS). Where histology specimens were not sent for review tumours were classified according to the local reporting histopathologist. For the purpose of survival analysis, GBM and GS were reported as one group and HG NOS have been reported separately.

Eligible patients required adequate hepatic, renal and haematological function, as specified for temozolomide [14Go, 15Go]. All patients had to be able to give informed consent and all signed an approved consent form, which was witnessed. The study was reviewed and approved by the Multicentre Research Ethics Committee and by local Research Ethics Committees before proceeding to accrual.

Temozolomide was administered prior to a standard 6-week course of radical radiotherapy at 200 mg/m2 for 5 days at 28-day intervals (dose was independent of anticonvulsant regimen) and was given for two cycles with standard anti-emetic cover. Patients who failed to complete two cycles of chemotherapy due to disease progression or neurological deterioration proceeded directly to radiotherapy, as clinically indicated, and were classified as progressive disease within the context of the study.

Patients had a contrast-enhanced CT or MRI scan after surgery, within 14 days of starting chemotherapy. Imaging response was assessed by comparing a second contrast enhanced CT/MRI (the same imaging as post-surgery scan) between days 14 and 28 of cycle two, prior to commencing radiotherapy.

All imaging was reviewed centrally. Images were digitised from hard copies and tumour size assessed by two independent observers (M.B. and G.P.). In case of discordant assessment a consensus was reached on review of images. Tumour size was assessed by measuring the product of the two largest perpendicular diameters of an enhancing mass on MRI or CT scan. Standard imaging criteria for response were used where complete response (CR) equated with the complete disappearance of all contrast enhancing tumour, partial response (PR) with ≥50% reduction in tumour size, minimal response (MR) as >25% and <50% reduction in size and progressive disease (PD) as ≥25% increase in the size of the contrast enhancing lesion. Any patient whose lesion did not meet the above criteria was considered as stable disease (SD).

If the pre-chemotherapy (after surgery) scan was suggestive of post-surgical change beyond that seen following biopsy alone an enquiry into the extent of surgery was initiated. Patients who had an attempted excision and some who had an open biopsy not assessable for response were excluded from the response analysis (Table 2). In the absence of second imaging, progression (PD) was defined as evidence of clinical progression prior to radiotherapy, discontinuation of the study drug due to clinical disease progression or neurological deterioration and death within 10 weeks of trial entry.


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Table 2. Overall and imaging response assessment

 
Radiotherapy was planned to commence a minimum of 2 weeks and a maximum of 6 weeks after day 1 of the second cycle of temozolomide, with a recommendation to start after day 28 of cycle two, in order to allow the maximum time for response assessment without compromising patient safety. Patients were recommended to receive conventional external beam radiotherapy to a dose of 55–60 Gy given in 30–33 fractions.

Clinical follow-up continued at 8-week intervals until death without the requirement for routine imaging.

Statistical considerations and safety
Delaying radiotherapy has the potential to allow for progression if test chemotherapy is ineffective. For safety reasons, the trial was therefore monitored after every 20 patients had completed temozolomide treatment and was designed to be stopped if there was good evidence (≥90% certainty) of a 40% progression/death rate on treatment.

Serious adverse events (SAEs) were defined according to the regulatory definition and were scored as any event that occurred within 28 days of the last dose of the study drug. The response rate was calculated as the proportion of assessable patients achieving a CR, PR or MR.

Survival was measured from the date of entry into the trial until death from any cause or last follow-up. Survival curves were calculated by the Kaplan–Meier method [22Go]; differences between subgroups were assessed by the log-rank statistic [23Go].

The independent significance of patient and disease characteristics on overall survival was investigated by means of the Cox proportional hazards model [24Go]. A step-up procedure with a 5% level of significance was used. Variables included in the model were those determined to be prognostic in the MRC prognostic index [25Go]. Response to temozolomide was then added to the final model.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study. One patient withdrew consent prior to commencing treatment and was withdrawn from the study; data on 187 patients were analysed. The median age was 55 years (range 20–77). A biopsy alone was performed in 171 (91%) patients with the remaining 16 (9%) undergoing an attempted partial excision. One hundred and thirty-seven patients (73%) had glioblastoma multiforme (GBM), 37 (20%) had AA, two (1%) had GS, and 11 (6%) glioma not otherwise specified (NOS). Central pathology review was undertaken in 124 (66%) cases. Patient and disease characteristics of the cohort are shown in Table 1.


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Table 1. Patient characteristics

 
One hundred and fifty-four (82%) patients received two complete courses of temozolomide. Of the 29 (18%) patients who discontinued chemotherapy, 24 (13%) did not receive the second cycle. Twenty-one stopped due to neurological deterioration, PD or early death (within 10 weeks of commencing chemotherapy) and three patients experienced an SAE that prevented the second course being administered. Five (5%) patients discontinued during the first cycle. Three patients withdrew consent to chemotherapy, one patient died and a further patient experienced an SAE which necessitated the discontinuation of temozolomide during the first cycle.

Imaging
The imaging of 126 patients was evaluable for response. Second scan was performed at a median of 49 days after initial scan (range 31–86 days). Surgical artefact precluded assessment of imaging response in four patients. Forty-two patients did not have a second scan; 36 because of clinical evidence of progression and six patients discontinued treatment without second scan for other reasons (Table 2). In 19 patients the second imaging was not assessable for technical reasons (Table 2).

There was concordance in response assessment between assessors in 87 out of 126 patients. In cases of discordant assessment a consensus decision was reached on review. Thirty-two patients had an imaging response with seven PR and 25 MR. Seventy-two patients had stable disease and 22 had progressive disease (Table 2).

Thirty-six patients did not have a second scan because of disease progression and were, therefore, not assessable for imaging response (Table 2). Fifteen patients did not receive a second cycle of temozolomide and proceeded directly with radiotherapy because of clinical evidence of progression. Of 21 patients who died, 12 died within 6 weeks of commencing temozolomide and nine died before the second scan could be performed, 6–10 weeks after commencing temozolomide.

Overall response
One hundred and twenty-six patients were assessable for response on imaging. Of 61 patients not assessable on imaging, 36 had clinical progression [death up to 10 weeks after starting chemotherapy (21 patients) and worsening neurological status (15 patients)]. In 25 patients (19%) no form of assessment, either radiological or clinical was possible. Overall, 162 patients were assessable for response; seven had PR and 25 MR. The overall response rate (PR and MR) was 20% [32 of 162 assessable patients; 95% confidence interval (CI) 14–26%], 72 patients (44%) had SD and 58 (36%) PD (Table 2). The respective overall response rates (PR and MR) were 14% (95% CI 1–26%) (four out of 29 assessable patients) for AA and 20% (95% CI: 11–30%) (25 out of 123 assessable patients) for GBM. There were no significant differences in response rate in patients on enzyme inducing anticonvulsants (PR and MR in 11 of 59 evaluable patients: 19%) and in patients not receiving these (PR and MR in 21 of 103 evaluable patients: 20%).

One hundred and four patients were free of progression at the time of second assessment prior to radiotherapy. The PFS in assessable patients was 64% (95% CI 57–72%). The respective PFS rates were 62% (95% CI 44–80%) for AA and 63% (95% CI 54–71%) for GBM.

Toxicity
Temozolomide was well tolerated. Fifty-three SAEs were reported; 26 required hospitalisation, seven were life threatening, 18 were deaths and two were a skin eruption and a steroid-induced psychosis which caused the cessation of treatment. Only five SAEs were considered by investigators to be related to temozolomide and all were related to recognised haematological toxicity, infection and a skin eruption that led to discontinuation of treatment. A further seven events were reported as possibly related to temozolomide, with three deaths (two due to pneumonia and one of unknown cause), one cardiac arrhythmia, one pulmonary embolism, one general weakness and one thrombocytopenia (Table 3).


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Table 3. Serious adverse events potentially attributable to temozolomide

 
Survival
At the time of analysis (April 2003) a total of 146 patients had died. Median survival of the cohort was 10 months with a 1-year survival of 41% and a 2-year survival of 17% (Figure 1). A univariate analysis for survival is shown in Table 4. Responders (MR and PR) had a median survival of 16 months compared to a median survival of 3 months for patients with PD, and a median survival of 12 months for patients with SD (Figure 2). Patients with AA had a median survival of 14 months and with GBM, 9 months (Figure 3).



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Figure 1. Survival of the cohort of 187 patients with malignant glioma.

 

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Table 4. Univariate and multivariate analysis of survival

 


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Figure 2. Survival by overall response.

 


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Figure 3. Survival by histology (high grade glioma not otherwise specified not included). AA, anaplastic astrocytoma; GBM, glioblastoma multiforme.

 
A multivariate analysis using the MRC prognostic index demonstrated age and performance status as independent predictors of survival (Table 4). After adjustment for prognostic factors, patients with PD had a significantly worse survival.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
Despite increasing use of systemic agents in the management of patients with malignant glioma, the impact of new treatments on outcome is limited. So far, only nitrosoureas have demonstrated survival benefit and this is of limited magnitude [3Go, 4Go]. Epidemiological studies have also not demonstrated improved survival outcome for the glioma population in recent years. The conclusion is that, despite a large number of trials assessing new systemic treatments, progress has been limited with little improvement beyond the results obtained with conventional surgery and radiotherapy.

The apparent lack of benefit of new treatments reflects, at least in part, the resistance of malignant glioma to systemic treatment. However, the study design to evaluate new treatments may also contribute, as it may not be sufficiently robust to detect promising new treatments and discard ineffective treatments. Failure to clearly identify poor performers means that ineffective treatments reach expensive, time consuming and ultimately negative phase III studies and consequently drain scarce research resources. We commenced a set of studies with the aim of more reliably identifying efficacy of a range of systemic treatments to allow a more informed selection of new agents for subsequent testing in phase III trials. This is particularly important at a time when increasing numbers of available agents require robust testing, either alone or in combination. A fast and reliable method of selection into broad efficacy bands is therefore desirable.

The need for new study design was also precipitated by the increasing knowledge of the unreliability of the methodology of assessing effectiveness of new treatments in patients with malignant glioma. The NCI consortium design of pre-radiotherapy testing does not fully deal with the confounding factor of the effect of surgery on the assessment of tumour size and the conventional phase II design at the time of recurrence does not address the unreliability of assessing imaging responses after previous therapy. While one solution is the use of survival as the primary endpoint, it is too much to expect for a new agent to show a significant impact on life expectancy in the setting of resistant disease where outcome is heavily influenced by pre-treatment prognostic variables. Eleven phase II studies and one phase III study have assessed systemic therapy in a neoadjuvant setting (Table 5). One study using temozolomide demonstrated an unusually high response rate including complete responses [21Go]. The large discrepancy may in part be explained by the confounding effect of surgery, which may have influenced the assessment of response. In addition, studies continued chemotherapy in patients not demonstrating progression and the larger chemotherapy exposure may have increased the response rate. As many of the studies do not provide data on the extent of surgical removal the precise reason for the difference is therefore not clear.


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Table 5. Summary of reported studies of neoadjuvant chemotherapy in malignant glioma

 
The new study design used in this study aimed at selecting patients with a histologically verified malignant glioma by biopsy alone so that little or no interference occurred with the enhancing tumour mass visible on imaging. While the requirement for study entry was minimal surgery (meaning biopsy alone), a proportion of patients (9%) were entered who clearly had more extensive surgical resection, which became apparent on baseline post-operative imaging. The assessment of size was not possible in this group of patients.

The primary endpoint for the assessment of efficacy in patients following biopsy uses a change in size of an enhancing lesion on imaging comparing scans prior to systemic treatment and at completion of two cycles before the start of radiotherapy. The rate of reduction in the size of the lesion following chemotherapy is not well defined and it is not clear whether the relatively short time interval between pre- and post-treatment imaging (6–8 weeks) is sufficient to detect a measurable change. To minimise inter-observer variation, all imaging was reviewed centrally by two observers. Temozolomide was chosen as the first agent to be tested because of its increasing popularity, ease of administration and the widely held perception that it may represent the current ‘gold standard’.

Although there is some degree of unreliability in the reported results, we have demonstrated imaging responses in a large cohort of patients treated in a uniform manner. In patients with malignant glioma the partial response rate to temozolomide was 4% and minimal response was 15%. The overall response rate was 20% (95% CI 14–26%). One hundred and four patients (64%; 95% CI 57–72%) were progression free after two courses of temozolomide. The meaning and value of response rate in gliomas can be questioned. Although we have demonstrated a relationship between response rate and survival giving some credence to this endpoint as a measure of efficacy, bias due to co-selection of favourable prognostic factors for survival with response cannot be excluded.

Although the response rate reported in this study is low, it does fall within the confidence intervals of the response rate reported in large phase II studies of temozolomide at the time of recurrence [14Go, 15Go, 19Go], with response rate in the region of 6–8% in recurrent glioblastoma and up to 34% in AA. In addition, the PFS of 64% is comparable to the progression free rate in the region of 60% assessed from 46% withdrawals in the neoadjuvant temozolomide study after two cycles of treatment [21Go].

The primary aim of this study was not the assessment of efficacy of temozolomide. It was designed to become a benchmark for further studies of chemotherapy using the same study design. In this respect, we have arrived at a response confidence interval which would indicate bands of efficacy in comparison to a standard. To have a 90% probability of detecting agents of similar effectiveness (>10% response rate) would require about 55 assessable patients. As the method of assessing response is not reliable, an alternative endpoint is a proportion of patients without progression following completion of chemotherapy. In our study, the PFS at second assessment was 64% (95% CI 57–72%). In future studies of alternative agents, about 50 assessable patients would be needed to detect a similar level (>55%) of PFS with 90% power.

We conclude that phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide with a response rate of 20% (95% CI 14–26%) and progression free rate of 64% (95% CI 57–72%) provide a benchmark for assessment of efficacy of other agents and combinations. Further studies employing this design are currently in progress.


    Addendum
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
Since the completion of this study, the use of concomitant and adjuvant temozolomide in the primary treatment of GBM has been shown to offer survival benefit (Stupp et al. 2005). This adds validity to the model with temozolomide as the appropriate comparative measure.

Stupp R, Mason WP, van den Beuf MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 2005; 352: 19–28.


    Acknowledgements
 
This study was supported by the Neuro-oncology Research Fund of The Royal Marsden NHS Trust. The Neuro-oncology Unit also received funding from Cancer Research UK and The Royal Marsden NHS Trust. The work was undertaken by the clinicians and hospitals listed below and we are grateful for their collaboration. UK hospitals receive a proportion of their funding from the NHS Executive; the views expressed are those of the authors and not necessarily those of the NHS Executive. Temozolomide was provided free of charge by Schering-Plough.

Study participants: M. Brada, F. Saran, The Royal Marsden NHS Trust; C. Elwell, Northampton General Hospital; S. Elyan, Cheltenham General Hospital; G. Gerrard, Cookridge Hospital; A. Gregor, Edinburgh Centre for Neuro-oncology; A. Hindley, S. Kumar, Royal Preston Hospital; O. Tilsley, Velindre Hospital; A. Lamont, Southend Hospital; K. Piggott, Royal Free Hospital; M. Reni, S Raffaele Scientific Institute, Milan; D.V. Vavassori, Ospedale di Circolo e Fondazione Macchi, Varese; J. Roberts, J. Bozzino, Northern Centre for Cancer Treatment, Newcastle General Hospital; C. Blesing, N. Warner, Churchill Hospital; S. Whitaker, St Luke's Cancer Centre, Royal Surrey County Hospital; D. Otim-Oyet, Derbyshire Royal Infirmary; H. Baillie-Johnson, Norfolk & Norwich Hospital; M. Sokal, Nottingham City Hospital; M. Wilkins, Royal Sussex County Hospital.


    Notes
 
{dagger} Present address: G. Pesce, Divisione di Radio-oncologia, Istituto Oncologico della Svizzera Italiana Ospedale San Giovanni, CH-6500 Bellinzona, Switzerland Back

Received for publication June 8, 2004. Revision received November 19, 2004. Accepted for publication November 19, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Addendum
 References
 
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