Initial results of hypoxia imaging using 1-α-d-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA)

  • Ernst J. Postema
  • Alexander J. B. McEwan
  • Terence A. Riauka
  • Piyush Kumar
  • Dacia A. Richmond
  • Douglas N. Abrams
  • Leonard I. Wiebe
Original Article

Abstract

Purpose

Tumour hypoxia is thought to play a significant role in the outcome of solid tumour therapy. Positron emission tomography (PET) is the best-validated noninvasive technique able to demonstrate the presence of hypoxia in vivo. The locally developed PET tracer for imaging hypoxia, 1-α-d-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA), has been shown to accumulate in experimental models of tumour hypoxia and to clear rapidly from the circulation and nonhypoxic tissues. The safety and general biodistribution patterns of this radiopharmaceutical in patients with squamous cell carcinoma of the head and neck (HNSCC), small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC), malignant lymphoma, and high-grade gliomas, were demonstrated in this study.

Methods

Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or high-grade gliomas were dosed with 5.2 MBq/kg of 18F-FAZA, then scanned 2–3 h after injection using a PET or PET/CT scanner. Images were interpreted by three experienced nuclear medicine physicians. The location and relative uptake scores (graded 0 to 4) of normal and abnormal 18F-FAZA biodistribution patterns, the calculated tumour-to-background (T/B) ratio, and the maximum standardized uptake value were recorded.

Results

Included in the study were 50 patients (32 men, 18 women). All seven patients with high-grade gliomas showed very high uptake of 18F-FAZA in the primary tumour. In six out of nine patients with HNSCC, clear uptake of 18F-FAZA was observed in the primary tumour and/or the lymph nodes in the neck. Of the 21 lymphoma patients (15 with non-Hodgkin’s lymphoma and 6 with Hodgkin’s disease), 3 demonstrated moderate lymphoma-related uptake. Of the 13 lung cancer patients (12 NSCLC, 1 SCLC), 7 had increased 18F-FAZA uptake in the primary lung tumour. No side effects of the administration of 18F-FAZA were observed.

Conclusion

This study suggests that 18F-FAZA may be a very useful radiopharmaceutical to image hypoxia in the tumour types selected. Especially the high uptake by gliomas was encouraging. Given the good imaging properties, including acceptable T/B ratios in the tumour categories studied, 18F-FAZA could be considered as a very promising agent for assessing the hypoxic fraction of these tumour types.

Keywords

Hypoxia Oncology Positron emission tomography 18F-FAZA 

Introduction

Tissue hypoxia is the result of an inadequate local oxygen supply. The results of this reduction in the partial pressure of oxygen are a cascade of molecular effects that compromise biological function [1]. Hypoxia may be diffusion-limited (chronic) or perfusion-limited (acute), with both mechanisms believed to be involved in the pathophysiology of cancer [1]. Compelling evidence now suggests that the presence of hypoxia induces cellular metabolic and proteomic changes that increase tumour aggressiveness and confer cellular resistance to both chemotherapy and radiation treatment. Multiple investigators have shown hypoxia – assessed by using intratumoral oxygen measurements – to be an adverse prognostic feature in several cancer types, including cervical carcinoma [2], squamous cell carcinoma of the head and neck (HNSCC) [3], and soft-tissue sarcoma [4]. Compounds based on nitroimidazole (azomycin) have played an important role in the assessment of oncological hypoxia, and retrospectively, have demonstrated the significance of oncological hypoxia in patient management [5, 6, 7].

Several techniques have been developed to measure the presence and extent of tumour hypoxia in vivo, ex vivo and in vitro. Since some of these require invasive procedures, either through the measurement itself or by obtaining a tissue sample for histological examination, the presence and extent of hypoxia is hardly ever assessed prior to treatment. The refinement of positron emission tomography (PET) techniques, the advantage of short half-life positron-based radionuclides and the development of hypoxia-specific positron-emitting radiopharmaceuticals (PERs) have made functional imaging of hypoxia a viable, noninvasive technique for clinical hypoxia imaging [8, 9, 10]. The molecule 1-α-d-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA) was invented and developed at the Cross Cancer Institute (Edmonton, Alberta) [11]. It is a 2-nitroimidazole-based molecule that undergoes reductive metabolism under hypoxic conditions, forming highly reactive intermediates that consequently bind to macromolecular cellular components. Preclinical studies have shown that 18F-FAZA is rapidly cleared from the circulation and nonhypoxic tissues, and is excreted mainly via the renal pathway, thereby providing more favourable tumour-to-background (T/B) ratios in most anatomical regions [12]. In contrast, 18F-FMISO, a chemically related but more lipophilic agent, is cleared primarily through the hepatobiliary route and undergoes nonspecific lipoidal uptake in the brain, liver and other organs, thereby interfering with the image quality in the region of interest (Hicks et al., unpublished data; [13]).

Given the potential advantages of 18F-FAZA for imaging hypoxia, a phase I/II study was initiated to demonstrate the safety of the 18F-FAZA drug product manufactured jointly by the Edmonton PET Centre and the Edmonton Radiopharmaceutical Centre, and to determine the general biodistribution pattern of this PER in patients with HNSCC, small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC), malignant lymphoma, or high-grade gliomas (astrocytoma and glioblastoma multiforme, GBM).

Materials and methods

Patients

Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or high-grade gliomas were eligible for inclusion. Patients had to be at least 16 years of age and have a Karnofsky performance scale score of at least 50. Female patients of child-bearing potential outside the window of 10 days since the first day of the last menstrual period had to have a negative pregnancy test. Nursing or pregnant patients could not be enrolled in the trial. The study protocol was approved by the Alberta Cancer Board Research Ethics Board (ETH 22390). All patients provided written informed consent prior to participation in the study.

Investigational product

18F-FAZA was manufactured according to Health Canada GMP regulations at the Edmonton PET Centre under the licence of the Edmonton Radiopharmaceutical Centre. 18F-FAZA radiosynthesis was performed using a TracerLab-FX automated synthesis unit (ASU) (GE Healthcare, Chalfont St. Giles, UK) placed in a Class 100 Comecer hot cell. 1-(2,3-Di-O-acetyl-5-O-tosyl-α-d-arabinofuranosyl)-2-nitroimidazole (5 mg) in anhydrous dimethyl sulfoxide (1 ml) was reacted with a mixture of azeotropically dried 18F-fluoride-Kryptofix 2.2.2 complex (15 mg; Sigma-Aldrich, St. Louis, MO) and anhydrous K2CO3 (3.5 mg) at 100°C for 5 min. Radiofluorinated product was subjected to alkaline hydrolysis using 0.1 N NaOH (1.0 ml, 2 min, 30°C) to remove protective acetyl groups and then the pH of this solution was adjusted to 5.5–7.5 by adding NaH2PO4 solution (0.4 M, 0.9 ml). The product was purified by reverse-phase high-performance liquid chromatography (C18 column) using ethanol/sterile water for injection (8/92, v/v) as an eluent at a flow rate of 2 ml/min. The 18F-FAZA-containing fraction was identified by monitoring the effluent at a wavelength of 320 nm (ultraviolet) and using radioactivity [NaI(Tl)] detectors, and was passed serially through an alumina cartridge and a sterile terminal filter (LG 22-μm pore size) before collecting in a sterile, nonpyrogenic, preweighed product vial. The product (about 1 GBq) was obtained in radiochemical yields of about 5%. Final product prerelease quality control included tests for radiochemical purity, chemical purity, radionuclidic purity, pH and pharmaceutical quality. Postrelease tests included determination of residual solvent (dimethyl sulfoxide) by gas chromatography (in house) and sterility and absence of bacterial endotoxin (contracted to an analytical company operating under ISO 9000 standards).

18F-FAZA was supplied in a sterile, nonpyrogenic multidose injection vial (20 ml) containing at least 1.0 GBq of 18F-FAZA in approximately 8 ml of sterile water for injection containing 8% ethanol. The required radioactive dose, i.e. 5.2 MBq/kg, was removed and diluted with physiological saline for injection to a total volume of 10 ml prior to intravenous administration. All doses were used within 12 h of calibration.

Study procedures

Prior to 18F-FAZA administration, patients were assessed for eligibility and weighed. In the first ten patients (phase I), preinjection blood pressure, heart rate, blood chemistry and haematology were measured for safety analysis. In each patient a shielded intravenous catheter was inserted into an appropriate peripheral vein, and each patient received a single intravenous injection of 5.2 MBq/kg of 18F-FAZA. Patients were permitted to eat, drink, and move within the confines of the Cross Cancer Institute for the 2 h preceding the PET scan. Immediately prior to imaging, patients were requested to void. Patients were monitored for any adverse events following the injection of 18F-FAZA.

Image acquisition and interpretation

Scanning began 2–3 h after injection. The first ten patients also underwent imaging 4–5 h after injection. This did not lead to improved image quality, nor did it lead to additional findings. Therefore, this additional scan was not performed in the remaining 40 patients. Images were collected for approximately 30–60 min in 8 to 11 bed positions of 3–4 min per bed position for a half-body scan, and for approximately 20 min for a brain scan, using either a Gemini PET/CT or an Allegro PET scanner (Philips, Best, The Netherlands). The emission scans were reconstructed using the 3-D row action maximum likelihood algorithm (RAMLA), and corrected for attenuation using either the CT scan (Gemini) or the 137Cs transmission scan (Allegro). 18F-FAZA PET scan images were visually examined by three experienced nuclear medicine physicians. Each physician was fully aware of the patient’s clinical history, including all results pertaining to other imaging tests, laboratory investigations, surgical and biopsy findings, pathology results and clinical course. The final interpretation of 18F-FAZA PET scan findings was achieved through discussion and consensus. The location and relative uptake scores (RUS) of normal and abnormal 18F-FAZA biodistribution patterns (RUS 0 indicates absent uptake; RUS 4 indicates very high uptake), the calculated T/B ratio, and the maximum standardized uptake value (SUVmax) were recorded.

Results

Included in the study were 50 patients (32 men, 18 women). The mean patient age was 59.1 years (range 18.2–90.0 years) and their mean weight was 82.8 kg (range 50–132 kg). Nine patients had HNSCC, 21 patients had lymphoma (15 with non-Hodgkin’s lymphoma and 6 with Hodgkin’s disease), 7 patients had high-grade glioma, and 13 patients had lung cancer (12 NSCLC, 1 SCLC). The Gemini PET/CT camera was used to image 33 patients, and the Allegro PET camera was used to image 17 patients.

Patients received a mean dose of 444.8 MBq 18F-FAZA (range 338–682 MBq). The radiation effective dose equivalents for patients in this protocol have been estimated to be 0.0123 mSv/MBq for male patients and 0.0165 mSv/MBq for female patients (unpublished data). Based upon the administered activities of 338–682 MBq, the effective radiation dose equivalents would be in the range 4.16–8.39 mSv for male patients and 5.58–11.25 mSv for female patients. No adverse events were noted during or following the administration of 18F-FAZA.

Table 1 shows the results of the scans in HNSCC patients. In five of nine patients, clear uptake of 18F-FAZA was observed in the primary tumour. In two of these patients, additional uptake was seen in the lymph nodes of the neck (Fig. 1, patient 18). One patient had uptake only in the neck and not in the primary tumour. Of the 21 lymphoma patients, 3 demonstrated some lymphoma-related uptake. Four other patients had some abnormal uptake as shown in Table 2, but not related to known lymphoma sites. No further diagnostic procedures were undertaken to investigate this unexpected uptake. All seven patients with high-grade gliomas showed very high uptake of 18F-FAZA in the primary tumour (Table 3, Fig. 2). Approximately half of the lung cancer patients (7 of 13) had increased 18F-FAZA uptake in the primary lung tumour (Table 4).
Table 1

18F-FAZA scan results in patients with HNSCC

Patient no.

Gender

Age (years)

Weight (kg)

Histology/site

PET or PET/CT

Abnormal uptake

Site of uptake

RUS

T/B ratio

SUVmax

02

Male

58.2

72

SCC of right tongue

PET/CT

No

    

03

Male

57.1

71

SCC of right tonsil

PET/CT

Yes

Right tonsil

3

2.1

1.74

Right neck

3

2.7

1.55

04

Male

52.2

132

SCC of left tongue

PET/CT

Yes

Left tongue

2

1.3

1.24

08

Male

51.1

116

SCC of left tongue

PET/CT

Yes

Left tongue

2

1.2

1.05

09

Male

58.9

103

SCC of left tongue

PET/CT

Yes

Left tongue

2

1.5

1.46

13

Male

63.5

104

SCC of left tongue

PET/CT

No

    

18

Male

73.6

61

SCC of right pyriform sinus

PET/CT

Yes

Larynx

4

1.8

1.60

Right neck

4

2.7

1.71

24

Male

55.5

73

SCC of pharynx

PET/CT

No

    

33

Female

74.8

62

SCC of epiglottis

PET

Yes

Right neck

3

1.4

2.35

Fig. 1

Uptake of 18F-FAZA in a patient with squamous cell carcinoma of the right pyriform sinus with a lymph node metastasis in the right neck (patient 18), as shown on PET and PET/CT images

Table 2

18F-FAZA scan results in patients with lymphoma

Patient no.

Gender

Age (years)

Weight (kg)

Histology

PET or PET/CT

Abnormal uptake

Site of uptake

RUS

T/B ratio

SUVmax

01

Female

44.3

75

Follicular lymphoma

PET/CT

No

    

05

Female

64.4

60

Follicular lymphoma

PET/CT

No

    

07

Male

25.0

95

Hodgkin's disease

PET/CT

No

    

10

Female

66.4

54

Follicular lymphoma

PET/CT

No

    

11

Female

52.0

89

Diffuse large B-cell lymphoma

PET/CT

No

    

14

Female

55.8

88

Small lymphocytic lymphoma

PET/CT

No

    

15

Male

71.3

94

Diffuse large B-cell lymphoma

PET/CT

Yes

Transverse colon

4

3.0

4.52

20

Male

19.0

77

Hodgkin's disease

PET/CT

Yes

Mediastinum

3

1.7

1.50

21

Male

24.7

107

Hodgkin's disease

PET/CT

No

    

28

Female

18.2

97

Hodgkin's disease

PET

No

    

30

Male

41.2

86

Hodgkin's disease

PET

No

    

31

Male

62.8

79

Diffuse large B-cell lymphoma

PET

No

    

32

Male

56.3

72

Diffuse large B-cell lymphoma

PET

No

    

34

Male

32.1

83

Diffuse large B-cell lymphoma

PET/CT

Yes

Mid-chest

1

1.2

1.07

35

Female

62.3

90

T-cell lymphoma

PET

No

    

37

Male

47.9

90

Diffuse large B-cell lymphoma

PET/CT

Yes

Right pleura

3

1.9

1.99

43

Female

38.3

78

Hodgkin's disease

PET

No

    

45

Male

55.0

98

Diffuse large B-cell lymphoma

PET

Yes

Gluteal

2

1.4

2.15

46

Female

59.9

63

Diffuse large B-cell lymphoma

PET

No

    

47

Male

62.8

101

Diffuse large B-cell lymphoma

PET

Yes

Supraclavicular

2

1.6

1.60

50

Female

87.1

58

Diffuse large B-cell lymphoma

PET

Yes

Right pelvis

2

1.3

2.23

Table 3

18F-FAZA scan results in patients with glioblastoma

Patient no.

Gender

Age (years)

Weight (kg)

Histology

PET or PET/CT

Abnormal uptake

Site of uptake

RUS

T/B ratio

06

Male

70.5

97

GBM

PET/CT

Yes

Left frontal lobe

4

2.8

12

Female

49.7

61

GBM

PET/CT

Yes

Left temporal lobe

4

2.7

19

Female

57.0

71

GBM

PET/CT

Yes

Left hemisphere

4

15.6

25

Male

72.5

73

GBM

PET/CT

Yes

Right frontal lobe

4

4.4

26

Male

80.9

90

GBM

PET/CT

Yes

Right temporal lobe

2

1.9

38

Male

59.7

106

GBM

PET

Yes

Left frontal lobe

4

5.2

40

Male

52.2

91

GBM

PET/CT

Yes

Right temporal lobe

4

4.4

Fig. 2

Increased uptake of 18F-FAZA in the glioma of patient 19, as shown on (a) coronal and (b) transverse PET images, and (c) coronal and (d) transverse PET/CT fusion images. Note the absent uptake of 18F-FAZA in the normal brain tissue

Table 4

18F-FAZA scan results in patients with lung cancer

Patient no.

Gender

Age (years)

Weight (kg)

Histology/site

PET or PET/CT

Abnormal uptake

Site of uptake

RUS

T/B ratio

SUVmax

16

Female

70.5

71

Adenocarcinoma/right lung

PET/CT

No

    

17

Male

90.0

92

Adenocarcinoma/left lung

PET/CT

Yes

Left upper lobe

2

1.4

1.10

Left lower lobe

2

1.3

1.29

22

Male

76.8

72

Squamous cell carcinoma/left lung

PET/CT

Yes

Left upper lobe

3

2.4

1.93

23

Female

49.1

64

Adenocarcinoma/right lung

PET/CT

Yes

Right lung

3

2.4

1.65

27

Male

78.6

66

Squamous cell carcinoma/right lung

PET/CT

Yes

Right upper lobe

2

2.0

0.96

29

Female

78.8

76

Squamous cell carcinoma/left lung

PET

No

    

36

Male

80.6

93

Small-cell carcinoma/right lung

PET

No

    

39

Male

81.7

50

Pancoast tumour/left lung

PET

Yes

Left upper lobe

3

2.4

1.49

41

Female

62.1

61

Adenocarcinoma/left lung

PET/CT

Yes

Left lower lobe

3

3.7

0.81

42

Male

63.0

88

Squamous cell carcinoma/left lung

PET

Yes

Left lower lobe

2

3.1

1.50

44

Male

66.5

115

Anaplastic large-cell carcinoma/right lung

PET/CT

No

    

48

Female

62.0

53

Adenocarcinoma/right lung

PET

No

    

49

Male

59.2

101

Squamous cell carcinoma/left lung

PET

No

    

In most cases, 18F-FAZA uptake was clearly visible due to the lack of background activity, especially in patients with gliomas, and in most of those with lung cancers. However, especially in the patients with lymphoma and HNSCC, an accompanying CT scan to correlate the uptake with an anatomical reference was very helpful to localize the uptake more precisely.

Discussion

18F-FAZA imaging in patients with high-grade gliomas provided striking images depicting putatively hypoxic regions in these tumours (Fig. 2). The high T/B ratios, which ranged from 1.9 to 15.6 (mean 5.3±4.7; Table 3), are attributable at least in part to the lack of uptake of 18F-FAZA by normal brain tissue. Recently, Spence et al. demonstrated, using 18F-FMISO in 22 patients, that volume and intensity of the hypoxic fraction of the GBM prior to radiotherapy strongly correlated with poor time-to-progression and survival [14], and other studies have also demonstrated that 18F-FMISO can show hypoxia in patients with GBM [15, 16, 17, 18]. Nonetheless, given the current data, 18F-FAZA seems to be an ideal candidate for assessment of hypoxia in GBM.

It is remarkable that, in a study in 11 patients with GBM, radioiodinated iodoazomycin arabinoside (123I-IAZA) was not retained in GBM [6]. This is surprising given the relatively high lipophilicity of 123I-IAZA, a property which correlates at least in part, to penetration of the blood–brain barrier [19]. Indeed, the uptake of 18F-FMISO, which is more lipophilic than 18F-FAZA but less lipophilic than 123I-IAZA, is a characteristic feature of all images of normal brains. In comparison to 18F-FMISO, uptake of 123I-IAZA in brain occurred in only approximately 40% of all patients studied. This uptake was attributed to radiation/chemotherapy-induced damage to the blood–brain barrier, since uptake occurred in only some patients, and was not correlated with any specific patient pathology. In our GBM study, which did not reveal uptake of 123I-IAZA in any of the gliomas [6], scans were obtained 24 h following injection of 123I-IAZA, whereas the 18F-FAZA PET images were obtained 2–3 h after injection. Apparently, 123I-IAZA is not retained in GBM over a 24-h time period, and early imaging is precluded by the relatively slow blood clearance.

It may be argued that the uptake of 18F-FAZA and other imaging agents in GBM is nonspecific and attributable to diffusion due to a disrupted blood–brain barrier. A disrupted blood–brain barrier might indeed play a role in the uptake of 18F-FAZA in gliomas – given the absent uptake of 18F-FAZA in normal brain tissue – but it does not explain the retention of the radiotracer. 18F-FAZA will only undergo reduction and be retained under hypoxic conditions. Evans et al. have recently shown that mild to moderate hypoxia is present in malignant gliomas [20]. They administered the 2-nitroimidazole agent EF5 – which has been developed, validated and tested as a quantitative hypoxia marker – to patients with brain tumours 24 h prior to resection of the tumour. The presence of hypoxia was assessed using anti-EF5 staining on resected material, and showed hypoxia in three grade 4 gliomablastomas, and no hypoxia in a haemangiopericytoma, an anaplastic oligodendroglioma and an oligoastrocytoma [20]. Given these findings and given the retention of 18F-FAZA in gliomas, we consider it likely that 18F-FAZA uptake in gliomas does represent hypoxia. Interestingly, the same group demonstrated a correlation between more rapid tumour recurrence and hypoxia in GBM using EF5 binding, but this relationship was not predicted by direct (Eppendorf electrode) measurements of oxygen concentration [21].

The present study also showed considerable 18F-FAZA uptake in tumours and/or lymph nodes in six out of nine patients with HNSCC. A pilot study conducted by the group of Piert in Munich showed a higher T/B ratio of 18F-FAZA in head and neck cancer patients than of 18F-FMISO [22]. Other investigators have already shown that hypoxia imaging can significantly contribute to treatment planning in patients with head and neck cancer. Grosu et al. showed that 18F-FAZA scanning could be used to plan external beam radiation treatment [7]. They described the location of hypoxic tumour using 18F-FAZA, followed by treatment planning in which hypoxic areas would receive higher doses – 80.5 Gy instead of 70 Gy – in order to achieve local control. In another study, an Australian group investigated the application of hypoxia imaging to monitor treatment with tirapazamine, a prodrug that is activated under hypoxic conditions [23, 24]. They showed excellent locoregional control in patients treated with tirapazamine, all of whom had positive 18F-FMISO scans prior to treatment [23]. Four weeks after initiation of treatment, a significant reduction in hypoxia, as assessed with 18F-FMISO scanning, was demonstrated [23]. Furthermore, patients with significant hypoxic fractions in the tumour, as seen on 18F-FMISO scans, had a higher risk of local failure when no tirapazamine was added to the treatment than those patients who did receive tirapazamine [24]. Data from the current study (Table 1) further support the use of 18F-FAZA for hypoxia imaging in patients with head and neck cancer.

Several PET tracers have been described for imaging hypoxia in lung cancer. Cherk et al. described the uptake of 18F-FMISO in 17 patients with NSCLC [25]. The authors stated that the uptake of 18F-FMISO was low in most patients, and concluded that NSCLC may be less hypoxic than other tumours. However, it is known that uptake of hypoxia imaging agents is not as high as one would expect when compared to the uptake of, for example, 18F-FDG, which was done in that study. Wong et al., using 62Cu-labelled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) [26], reported high lung tumour radioactivity, with an SUVmax of 2.7. 18F-labelled 1-(2-fluoro-1-[hydroxymethyl]-ethoxy)-methyl-2-nitroimidazole (18F-FRP170) was used by the group of Yasuda et al. in a population of nine geriatric patients with NSCLC [27], and they showed the feasibility of this tracer for hypoxia imaging. The results of our study are in keeping with the aforementioned studies, in suggesting that 18F-FAZA could play a role in imaging hypoxia in lung tumours. However, none of the tracers described have been used to evaluate how hypoxia imaging could be used to modify treatment of lung cancer. We are currently conducting a trial using 18F-FAZA to evaluate the change of the hypoxic fraction of lung tumours following treatment with external beam radiation.

Hypoxia imaging of lymphoma patients has not been reported to date. In our study, the majority of lymphoma patients did not show extensive or high uptake of 18F-FAZA. In only three patients was uptake of 18F-FAZA seen in lymphoma sites. One-year follow-up of those three patients revealed that two had responded well to the treatment and were disease-free, whereas one patient had a remission half a year after the treatment. Since the role of tumour hypoxia imaging in the management of lymphoma is unclear, and given the relatively low or absent uptake of 18F-FAZA in most lymphoma sites of this study population, it remains uncertain if there is a role for hypoxia imaging in this category of patients.

The suitability of 18F-FAZA for the imaging of hypoxia in cancer of the uterine cervix has not been studied in our centre so far. A recent study by Dehdashti et al. has shown the usefulness of 60Cu-ATSM to predict the progression-free survival in patients with cervical cancer [28]. The 3-year progression-free survival in the group of patients with hypoxic tumours, defined as a tumour-to-muscle ratio of the 60Cu-ATSM uptake of >3.5, was only 28%. Patients with a tumour-to-muscle ratio of ≤3.5 did significantly better, with a 3-year progression-free survival of 71%. Future studies with 18F-FAZA should certainly include patients with cervical cancer to investigate its usefulness in this group of patients.

Conclusion

It is feasible and safe to use 18F-FAZA for clinical hypoxia imaging in a variety of tumour categories, particularly HNSCC, lung and GBM tumours. Given the good imaging properties with acceptable T/B ratios in the patient categories described, 18F-FAZA seems to be a very favourable hypoxia imaging agent, especially for gliomas. Future trials are required to implement treatment planning based on image-derived knowledge of the hypoxic fraction of tumours.

Notes

Acknowledgments

The authors would like to thank the Regulatory Team – Margaret Landon, Sandra Gordey, Lai Schrader, Robert McQuarrie, and Merlita Lamadrid – of the Department of Oncologic Imaging at the Cross Cancer Institute for all their efforts collecting and processing the data. We would also like to thank the attending physicians of the Cross Cancer Institute, and Drs. Andrew Belch and Matthew Parliament in particular, for their ongoing support of this trial.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ernst J. Postema
    • 1
  • Alexander J. B. McEwan
    • 1
  • Terence A. Riauka
    • 1
  • Piyush Kumar
    • 1
  • Dacia A. Richmond
    • 1
  • Douglas N. Abrams
    • 1
  • Leonard I. Wiebe
    • 2
  1. 1.Department of OncologyUniversity of AlbertaEdmontonCanada
  2. 2.Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmontonCanada

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