A phase I dose-escalation study of docetaxel with granulocyte colony-stimulating factor support in patients with solid tumours

P. L. R. Mitchell1,+, R. Basser2, M. Chipman1, A. Grigg3, J. Cebon1, I. D. Davis1, J. Zalcberg1, S. Ng3, F. Appia4,5 and M. Green3

Centre for Developmental Cancer Therapeutics at 1 Austin and Repatriation Medical Centre, 2 Western Hospital and 3 Royal Melbourne Hospital, Melbourne, Victoria; 4 Aventis, Melbourne, Victoria, Australia; 5 Aventis, Paris, France

Received 11 July 2002; revised 21 November 2002; accepted 3 December 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Docetaxel is a widely active cytotoxic agent. The principal dose-limiting toxicities (DLTs) of the 3-weekly regimen are neutropenia and febrile neutropenia. Use of prophylactic granulocyte colony-stimulating factor (G-CSF) may allow higher doses of docetaxel to be administered with potentially greater anticancer efficacy. The objectives of this study were to determine the maximum tolerated dose (MTD) and toxicity profile of docetaxel given with G-CSF support.

Patients and methods:

Eligible patients had solid tumours and were aged 18–75 years with a WHO performance status of up to 2. Strict criteria for liver function were followed. Patients may have received one previous regimen of chemotherapy in addition to adjuvant chemotherapy. Cohorts of three to six patients received docetaxel over 60–90 min every 3 weeks, commencing at 110 mg/m2 and escalating at 10 mg/m2 increments. Patients also received G-CSF 5 µg/kg/day until neutrophil recovery. A 3-day corticosteroid prophylaxis was given.

Results:

Twenty-nine patients with median age 55 years (range 29–75) were included. Fourteen (48%) had previously received chemotherapy. At the 170 mg/m2 dose level (the MTD), two of three patients had DLTs and 160 mg/m2 was determined to be the recommended dose. The principal DLTs were skin and neurosensory toxicity. Asthenia was frequent, especially at dose levels >=140 mg/m2. Grade 4 neutropenia occurred in only 10 patients (35%) and was not dose related, with febrile neutropenia in three patients (10%).

Conclusions:

Docetaxel may be escalated considerably above standard doses when administered with G-CSF support. The recommended dose for phase II studies is 160 mg/m2. With escalated-dose docetaxel, DLTs were non-haematological and qualitatively similar to the toxicity profile at standard doses.

Key words: docetaxel, dose escalation, granulocyte colony-stimulating factor, phase I, toxicity


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Docetaxel is a semi-synthetic taxoid which targets intracellular tubulin. From phase I studies, the recommended dose of 3-weekly docetaxel is 100 mg/m2 given over 1 h and the principal dose-limiting toxicity (DLT) is neutropenia [1, 2]. Other toxicities with this schedule, which have not been dose limiting, include hypersensitivity reactions, mucositis, fluid retention, peripheral neuropathy and skin toxicity. However, there is evidence that at least some of these toxicities may be prevented or ameliorated by prophylactic administration of corticosteroids [35].

When administered prophylactically following chemotherapy, granulocyte colony-stimulating factor (G-CSF) reduces both the depth and the duration of the neutrophil nadir, and has been shown to approximately halve the rate of febrile neutropenia [6]. G-CSF has been widely used in dose-escalation of chemotherapy agents [7]. Docetaxel at standard doses of 75–100 mg/m2 is active in a range of malignancies and may have enhanced activity at higher doses. Although the DLT of docetaxel with a 3-weekly schedule was neutropenia, the potential for dose-escalation with G-CSF has not been systematically explored. The objectives of this study were to determine the maximum tolerated dose (MTD) and DLT, as well as the recommended dose for further studies of the combination.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The trial was carried out by the Centre for Developmental Cancer Therapeutics (CDCT) research group in Melbourne, Australia with the participation of the Austin and Repatriation Medical Centre, and the Royal Melbourne and Western Hospitals.

Patients with solid tumours, but without brain or meningeal metastases, were eligible. Age was 18–75 years and WHO (World Health Organization) performance status (PS) was up to 2. Baseline neurosensory changes were required to be grade <=1, neutrophils >=1.5 x 109/l, platelets >=100 x 109/l, haemoglobin >=10 g/dl and serum creatinine <1.5x upper normal limit (UNL).

The eligibility criteria for hepatic function were as follows: total bilirubin <=1x UNL or <=1.5x UNL if aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were normal; AST and ALT <=2.5x UNL; ALP <=5x UNL (except in the absence of liver metastases and presence of bone disease). Patients with both ALP >2.5 x UNL and AST or ALT >1.5x UNL were not eligible. Patients with significant psychiatric or medical illnesses were not eligible.

Patients must not have received high-dose chemotherapy. Prior therapy with chemotherapy, hormonal therapy or radiotherapy must have been completed at least 4 weeks previously and total radiotherapy must have been to <=30% of marrow-bearing areas. No more than one prior chemotherapy regimen for advanced disease, in addition to any adjuvant chemotherapy, was allowed. Patients gave written informed consent and the study was approved by the Institutional Ethics Committees of participating hospitals.

At baseline the following investigations were undertaken: history and physical examination; electrocardiogram; full blood count (FBC); electrolytes; renal and hepatic function; calcium and random glucose. FBC was checked three times per week from day 8 until neutrophil recovery, then weekly. If a patient had grade 4 neutropenia at day 8 of cycle 1, then FBC was checked from day 6 for subsequent cycles. Baseline imaging investigations included a chest X-ray and also a computed tomography (CT) scan of disease sites. The CT scan was repeated after three and six cycles. Confirmation of an objective response after at least 4 weeks was required.

Treatment and study design
Cohorts of three to six patients received escalating doses of docetaxel, commencing at 110 mg/m2 with successive cohorts escalated by 10 mg/m2. There was no escalation of doses for individual patients and a maximum of six cycles was given. Docetaxel was administered as a 1-h infusion every 3 weeks. The infusion duration was increased to 90 min where individual doses were >240 mg. A total of six doses of oral dexamethasone 8 mg were given at the following times: the evening before treatment; the morning of, and 1 h before, treatment; the evening after treatment; the morning and evening of the next day.

Patients received G-CSF (lenograstim; Aventis, Paris, France) 5 µg/kg as a daily subcutaneous injection, commencing the day after chemotherapy and continuing until neutrophils were >=1.0 x 109/l.

Doses were to be escalated until the MTD was reached. This was defined as the dose where three or more of six patients experienced DLTs during the first cycle. Toxicities occurring during later cycles could also be considered DLTs if particularly severe, in case there was early onset of severe toxicities usually associated with a cumulative dose, particularly neurotoxicity or skin toxicity. Once the MTD was reached, further patients were to be recruited to the level immediately below to complete a cohort of six patients at that dose level. Further dose-escalation was then allowed, including only patients who had not previously received chemotherapy for advanced disease. This allowed determination of a second MTD for chemotherapy-naive patients should the first MTD include predominantly pretreated patients.

Toxicities were graded using the National Cancer Institute Common Toxicity Criteria, version 1.0. The following toxicities were considered DLTs: platelets <25 x 109/l, prolonged febrile neutropenia (defined as grade 4 neutropenia with fever >=38.5°C on one occasion or 38°C on three occasions during a 24-h period) persisting for >=3 days despite intravenous antibiotics, grade 3/4 infection, or failure to recover neutrophils >=1.5 x 109/l or platelets >=100 x 109/l by day 28. Neurosensory DLT was initially defined as grade >=2 during cycle 1. However, this was amended to avoid mild or transient objective sensory loss being considered dose limiting, and following recruitment of the initial 18 patients neurosensory DLT was redefined as grade >=3 at any time, or failure to recover to grade <=1 by day 28. Grade 3 nausea or diarrhoea or grade 4 vomiting were DLTs if they occurred despite adequate prophylaxis. Other non-haematological DLT were any grade >=3 toxicity, with the exception of anaemia or alopecia.

Docetaxel was administered every 21 days provided the neutrophil count was >=1.5 x 109/l and platelets >=100 x 109/l. Patients requiring more than 7 days for recovery of toxicities were removed from the study. Dose reductions of 20 mg/m2 were made for the following toxicities: febrile neutropenia persisting for >=3 days despite intravenous antibiotics; platelet nadir <25 x 109/l; grade >=3 skin toxicity or grade >=2 neuropathy. Patients with persisting grade >=2 skin or neurosensory toxicity after a 1 week delay were to go off study. If grade >=3 nausea, vomiting or diarrhoea occurred, patients received appropriate prophylaxis for the next cycle and if grade >=3 toxicity recurred a 20 mg/m2 dose reduction was made. If bilirubin became elevated above the baseline level, patients went off study if this did not recover to baseline by day 28. A 25% dose reduction occurred for abnormal hepatic function (AST and/or ALT >=2.5x UNL or ALP >=2.5x UNL) measured at the time treatment was due. With AST and/or ALT >5x UNL or ALP >5x UNL, 1 week was allowed for recovery to below these levels, after which time patients without recovery went off study. Other grade 3/4 toxicity required delay until recovery to grade <=1 and a 10 mg/m2 dose reduction was subsequently made. No dose reductions were made for allergic reactions, peripheral oedema or effusions, or alopecia.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-nine patients were enrolled on study. All were evaluable for toxicity and 27 evaluable for efficacy (Table 1). Median age was 55 years and PS 0 or 1 except for four patients (14%). Fourteen patients (48%) had previously received chemotherapy (10 for advanced disease and four patients both as adjuvant and for advanced disease).


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Table 1.  Patient characteristics (n = 29)
 
Dose-limiting toxicity
DLTs were seen at the 130 and 170 mg/m2 dose levels (Table 2). As DLTs were seen in two of the first three patients at the 130 mg/m2 level, this cohort was expanded to six patients but no further DLTs were seen. The first patient with DLT at 130 mg/m2 had previously received carboplatin and cyclophosphamide chemotherapy for stage IV gastric cancer and had a PS of 1. This patient had grade 3 skin toxicity during the first cycle with erythema and desquamation involving the forearms and hands. However, the skin toxicity improved quickly, resolving to grade 1 by day 21 and treatment continued to six cycles with a dose reduction to 110 mg/m2 without recurrence of skin toxicity. The second patient with a DLT at the 130 mg/m2 level had received cisplatin and 5-fluorouracil for stage IV pharyngeal cancer and had a PS of 1. At baseline there was grade 1 neurosensory changes. This patient had grade 3 neurosensory toxicity during cycle 2, which improved to grade 1 in 15 days and the patient went on to receive four further cycles at a reduced dosage of 100 mg/m2. There was no further recurrence of grade 3 neurotoxicity. This patient also had a transient grade 3 elevation of ALT during cycle 2, which did not recur at reduced dosage.


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Table 2.  Dose-limiting toxicities (DLTs)
 
Escalation of doses then continued to the 170 mg/m2 level. At this level, two of three patients experienced DLTs during the first cycle (Table 2). The first patient with a DLT at this level had a PS of 1 with adenocarcinoma of the lung. Painful grade 3 neurosensory toxicity developed at day 6 of the first cycle and did not improve for 3 months. Severe, grade 3 asthenia also developed during the first cycle. This patient was removed from the study. A second patient with DLT had stage IV gastric cancer and a PS of 2. This patient had grade 3 skin toxicity with erythema and bullous eruption on the hands and forearms. The skin toxicity improved to grade 1 and further treatment was given with a dose reduction to 150 mg/m2. As these DLTs occurred during the first cycle it was decided not to expand the cohort, particularly as one patient had severe prolonged neurotoxicity, although the predefined criteria for the MTD had not been strictly satisfied. Also, a second MTD for chemotherapy-naive patients did not need to be established as all three patients at the 170 mg/m2 level were chemotherapy-naive. The 160 mg/m2 dose level was then expanded to six patients, without DLTs at that level, and was determined to be the recommended dose for further studies.

Treatment
Patients received a median of four cycles of docetaxel (range one to six), with a median total dose delivered of 468 mg/m2 and range 170–947 mg/m2 (Table 3). Twenty cycles were given to patients at the recommended dose level of 160 mg/m2. The reasons for discontinuing therapy were as follows: completion of planned therapy in six patients, progressive disease in 13 and toxicity in nine. One patient refused treatment beyond four cycles due to no objective response. In those discontinuing due to toxicity, discontinuation occurred after a median of three cycles and the most frequent toxicities were asthenia, skin or nail toxicity, or neurosensory toxicity (Table 4).


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Table 3.  Number of cycles of docetaxel delivered to patients at each dose level
 

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Table 4.  Numbers of patients failing to complete protocol treatment due to toxicity or with dose reductions
 
The relative dose intensity (RDI) was 0.98 (of the planned dose). The four patients (14%) with dose reductions had RDIs of 0.81, 0.83, 0.94 and 0.94. These patients were treated at the 120, 130 (two patients) and 170 mg/m2 dose levels.

Adverse events
The frequency of patients with adverse events during any cycle is shown in Table 5. There were no treatment-related deaths. Only 10 patients (35%) developed grade 4 neutropenia at any time during multiple cycles of docetaxel. An additional three patients had grade 3 neutropenia. There was no relationship between neutropenia and the dose administered. Grade 3/4 neutropenia occurred during 11 of the 52 cycles (21%) with a dose <=130 mg/m2 compared with 13 of 59 cycles (22%) with a dose >=140 mg/m2. The median time to neutrophil nadir was 6 days (range 4–13 days) and the median duration of G-CSF administration was 6 days.


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Table 5.  Adverse events during multiple cycles of docetaxel
 
Febrile neutropenia was seen in three patients (10%), including one patient each from the 130, 150 and 160 mg/m2 cohorts. Five patients had grade 3 infection in the absence of significant neutropenia, with nail infections in two and one patient each with urinary infection, chest infection and central line infection. These five patients included one patient each from the 120, 130, 140, 150 and 170 mg/m2 cohorts. In addition, eight patients (28%) had fever in the absence of neutropenia, which was grade 2 (<40°C) in seven patients and grade 3 (>40°C) in one patient. This was most frequently observed 3–4 days following administration of docetaxel, and became a recurring pattern for some individual patients with multiple cycles.

The most frequent non-haematological toxicity was asthenia (Table 5), seen in 26 patients (90%). Grade 3 asthenia developed in 13 patients (45%). This tended to be worse in the days after treatment and also tended to get worse with multiple cycles. Asthenia also occurred more frequently at higher doses of docetaxel. Grade 3 asthenia occurred with three of the 52 cycles (6%) with a dose <=130 mg/m2 as compared with 12 of 59 cycles (20%) with a dose >=140 mg/m2. There was no grade 3 peripheral oedema, while grade 2 oedema occurred in nine patients (31%) with a median cumulative dose to onset of 420 mg/m2. Neurosensory toxicity was grade 3 in three patients, with onset after cumulative doses of 170, 260 and 840 mg/m2, respectively. An additional 17 patients (59%) had grade 1/2 neurosensory toxicity. Two patients had grade 3 skin toxicity. Nail toxicity was frequent, seen in 16 patients (55%). More severe, grade 3 nail disorders, specifically onycholysis with or without nail infection, were seen in four patients (14%).

Fifteen patients (52%) were hospitalised on a total of 32 occasions for events considered to be related to study therapy. The most frequent causes of hospitalisation were infection (eight episodes in six patients) and fever in the absence of infection (11 episodes in five patients).

Antitumour efficacy
Twenty-six patients were evaluable for efficacy. A partial remission was seen in nine patients (35%) and was confirmed in six of these. A partial remission was defined as a >=50% reduction in the sum of the products of two perpendicular diameters of the target lesions. Patients with confirmed partial responses included two of the four patients with breast cancer (both pretreated with doxorubicin and cyclophosphamide), one of the five patients with carcinoma of unknown primary (no prior chemotherapy), and each of the single patients with pancreatic cancer (no prior chemotherapy), oesophageal carcinoma (prior cisplatin and 5-fluorouracil) and nasopharyngeal carcinoma (prior cisplatin).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Docetaxel has become a widely used cytotoxic agent in a range of malignancies, including breast cancer [8, 9], non-small-cell lung cancer [1012] and ovarian cancer [13]. Despite widespread use, the potential for dose-escalation of docetaxel has not been systematically explored.

Phase I studies of docetaxel investigated a number of schedules. With multiday regimens and longer infusion times the principal DLTs were mucositis and neutropenia [1416]. A different toxicity profile was seen where a short infusion was administered every 2–3 weeks, with less mucositis while neutropenia remained dose limiting. The highest dose cohort reached was 125 mg/m2 in these phase I studies [1, 2]. The 3-weekly 1-h infusion schedule was chosen for further development, with a dose of 100 mg/m2. However, this schedule and dose has appreciable rates of haematological toxicity and febrile neutropenia. Despite widespread use of the 3-weekly regimen and the known haematological toxicity profile, strategies for the reduction of neutropenia and its complications have only recently been explored. This has, in part, been due to important non-haematological toxicities such as skin toxicity and fluid retention occurring at the recommended dose. However, the reduction of non-haematological toxicities, particularly fluid retention, by the use of corticosteroid prophylaxis, suggested that the dose of docetaxel might be escalated with cytokine support [35].

In this study, G-CSF was given in combination with docetaxel, aiming to dose-escalate while minimising the risk of neutropenia and neutropenic sepsis. A 3-day corticosteroid prophylaxis was given to reduce non-haematological toxicity. A conservative dose-escalation schedule, with 10 mg/m2 increments, was used in view of the known high rate of febrile neutropenia at standard doses and as a previous study had suggested that increased exposure to docetaxel was associated with significantly increased toxicity [17]. As a high incidence of neutropenia was expected in the current study, the criteria for DLT did not include severe neutropenia, or brief febrile neutropenia.

One of the two patients with DLTs at the 130 mg/m2 dose level had grade 3 neurosensory DLT. This patient had grade 1 neurosensory changes at baseline that may have predisposed to severe neurosensory toxicity with docetaxel. At the 170 mg/m2 dose level, DLTs was seen in two of the three patients, all of whom were chemotherapy-naive. The dose level was not further expanded as the toxicities were severe and occurred during the first cycle, with very prolonged grade 3 neurosensory neuropathy in one patient and severe skin toxicity in another. Consequently, 170 mg/m2 was determined to be the MTD, and further patients were recruited to the 160 mg/m2 level to complete a cohort of six patients at that level. No DLT was seen at the 160 mg/m2 level and this was determined to be the recommended dose for further study. At the 160 mg/m2 dose level, grade 3/4 neutropenia was seen in three of six patients, while the most frequent severe non-haematological toxicity was grade 3 asthenia seen in three patients. Asthenia was not considered dose limiting in these patients as it occurred towards the end of the course of docetaxel.

All patients received the planned doses of docetaxel except for four patients (14%) who had dose reductions for toxicity. Nine patients, from a range of dose cohorts, did not complete protocol treatment due to adverse events, which included asthenia, skin and nail toxicity, gastrointestinal side-effects, neurosensory toxicity, allergic reactions and oedema.

The study was noteworthy for a low rate of haematological toxicity. At the standard dose of docetaxel, 100 mg/m2, without cytokine support, the incidence of grade 4 neutropenia has been reported to be 48–64% [11, 17, 18], with febrile neutropenia occurring in 12–25% of patients [10, 11, 19]. The haematological toxicity of docetaxel would appear to be dose related, with grade 4 neutropenia increasing from 54% to 77% and febrile neutropenia from 8% to 12% where the dose of docetaxel was increased from 75 to 100 mg/m2 [11]. Despite escalation of the dose of docetaxel, in the current study only 10 patients (34%) had grade 4 neutropenia during any cycle. The incidence of grade 4 neutropenia with G-CSF support was not found to be related to dose, with a similar incidence in cycles with doses up to 130 mg/m2 as in cycles at higher doses. Only three patients (10%) had febrile neutropenia. G-CSF was clearly effective in reducing what might be expected to be an increased incidence of these toxicities.

The low rate of febrile neutropenia may have, in part, been related to the strict inclusion criteria for liver function. Abnormal liver function tests have been associated with reduced docetaxel clearance [17] and a high rate of both febrile neutropenia and moderate or severe mucositis [19].

G-CSF has been administered in a number of phase II studies where docetaxel 100 mg/m2 was given 3-weekly and rates of severe neutropenia and febrile neutropenia have generally been lower than those reported in trials without G-CSF. These studies did not investigate dose-escalation. No grade 4 neutropenia was seen in a small study of patients with non-small-cell lung cancer [20], and in a study of pancreatic cancer, grade 4 neutropenia was seen in 24% of patients and febrile neutropenia in 6% of patients [21]. G-CSF support has also been used in a study of gastric cancer patients with grade 3/4 neutropenia occurring in 36% and febrile neutropenia in 10% [22]. In a further study of 60 patients with lung cancer, the 23% rate of grade 4 neutropenia was low; however, 30% of patients had febrile neutropenia [23].

The DLTs in the current study were non-haematological, specifically skin and neurosensory toxicity. Less severe skin toxicity and neurosensory toxicity were also frequent, with grade 1/2 toxicity in 62% and 59% of patients, respectively. No severe fluid retention was seen although grade 1/2 retention occurred in 41% of patients. In studies of patients receiving standard- dose docetaxel, fluid retention has been reported in ~60% of corticosteroid-pretreated patients and was severe in ~6% [24]. Nail toxicity was frequent and seen in 55% of patients, with grade 3 changes in four patients (14%). These patients developed onycholysis with, or without, infection. Nail changes have been described with standard-dose docetaxel [2528]. However, the most frequent non-haematological toxicity was asthenia, which was grade 3 in 13 patients (45%), while a similar number of patients had grade 1/2 asthenia. Asthenia became more severe with multiple cycles and occurred more frequently at the higher doses of docetaxel. Severe asthenia was seen with 6% of cycles at doses of <=130 mg/m2 compared with 20% of cycles given at higher doses. Severe asthenia after multiple cycles of docetaxel >=140 mg/m2 may limit the usefulness of this regimen. Asthenia is a DLT with the weekly docetaxel schedule [29].

Approximately half of patients were hospitalised in the current study. However, a third of these patients were hospitalised for fever in the absence of infection or significant neutropenia. It is not clear whether fever was due to docetaxel or G-CSF. Many patients with fever were hospitalised for observation and did not receive antibiotic therapy and it is likely that at least some of these hospitalisations might have been avoided.

There have been few studies where the dose of docetaxel has been escalated. In an early phase I study, doses were escalated to 125 mg/m2 without G-CSF support and dose-limiting neutropenia, and neutropenic sepsis was seen at this level [2]. A study has been reported in abstract form where docetaxel was escalated with G-CSF to 120 mg/m2 [30].

Dose-escalation studies of docetaxel have been carried out in paediatric patients. Dose-related neutropenia was the primary DLT without cytokine support [31]. With G-CSF support, neutropenia was not dose limiting and, as in the current study, was not dose related. Generalised erythematous desquamating skin rashes and myalgias were dose limiting at 235 mg/m2. The recommended dose of docetaxel with G-CSF in paediatric patients was 185 mg/m2 [32].

In adult patients, dose-limiting skin and neurosensory toxicities were seen at docetaxel 170 mg/m2, given with G-CSF support. At the recommended dose of 160 mg/m2, no DLTs were seen and the haematological toxicity and febrile neutropenia profile was acceptable and less than seen at standard doses without G-CSF support. Asthenia was the most frequent non-haematological toxicity, especially with docetaxel doses >130 mg/m2. Further studies of escalated-dose docetaxel with G-CSF support are warranted to investigate whether these higher doses translate into greater clinical effectiveness. A phase II study of docetaxel 160 mg/m2 in patients with advanced breast cancer is being carried out by the CDCT group.


    Acknowledgements
 
This work was supported in part by Aventis Pharmaceuticals.


    Footnotes
 
+ Correspondence to: Dr P. L. R. Mitchell, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Melbourne, Victoria 3084, Australia. Tel: +61-3-9496-3338; Fax: +61-3-9496-3379; E-mail: paul.mitchell{at}armc.org.au Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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