Eur J Nucl Med Mol Imaging (2009) 36:1565–1573 DOI 10.1007/s00259-009-1154-5
ORIGINAL ARTICLE
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
Received: 9 January 2009 / Accepted: 17 April 2009 / Published online: 9 May 2009 # Springer-Verlag 2009
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 18FFAZA, 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 E. J. Postema (*) : A. J. B. McEwan : T. A. Riauka : P. Kumar : D. A. Richmond : D. N. Abrams Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada e-mail:
[email protected] L. I. Wiebe Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada
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 lymphomarelated 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 18FFAZA 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
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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 [5–7]. 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 [8–10]. The molecule 1-α-D -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2nitroimidazole (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-tobackground (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).
Eur J Nucl Med Mol Imaging (2009) 36:1565–1573
Materials and methods
Patients Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or highgrade 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 18
F-FAZA was manufactured according to Health Canada GMP regulations at the Edmonton PET Centre under the licence of the Edmonton Radiopharmaceutical Centre. 18FFAZA 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 18Ffluoride-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-FAZAcontaining 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).
Eur J Nucl Med Mol Imaging (2009) 36:1565–1573 18
F-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 137 Cs 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 (SUV max) were recorded.
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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 lymphomarelated 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). 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 18
F-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-
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Eur J Nucl Med Mol Imaging (2009) 36:1565–1573 18
F-FAZA scan results in patients with HNSCC
Patient no.
Gender
Age (years)
Weight (kg)
02 03
Male Male
58.2 57.1
72 71
Histology/site
SCC of right tongue SCC of right tonsil
PET or PET/CT
Abnormal uptake
PET/CT PET/CT
No Yes
04
Male
52.2
132
SCC of left tongue
PET/CT
Yes
08
Male
51.1
116
SCC of left tongue
PET/CT
Yes
09
Male
58.9
103
SCC of left tongue
PET/CT
Yes
13 18
Male Male
63.5 73.6
104 61
SCC of left tongue SCC of right pyriform sinus
PET/CT PET/CT
No Yes
24 33
Male Female
55.5 74.8
73 62
SCC of pharynx SCC of epiglottis
PET/CT PET
No Yes
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-toprogression and survival [14], and other studies have also demonstrated that 18F-FMISO can show hypoxia in patients with GBM [15–18]. Nonetheless, given the current data, 18 F-FAZA seems to be an ideal candidate for assessment of hypoxia in GBM.
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
Site of uptake
RUS
T/B ratio
SUVmax
Right tonsil Right neck Left tongue Left tongue Left tongue
3
2.1
1.74
3
2.7
1.55
2
1.3
1.24
2
1.2
1.05
2
1.5
1.46
Larynx Right neck
4 4
1.8 2.7
1.60 1.71
Right neck
3
1.4
2.35
It is remarkable that, in a study in 11 patients with GBM, radioiodinated iodoazomycin arabinoside (123IIAZA) 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 18FFMISO, 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,
Eur J Nucl Med Mol Imaging (2009) 36:1565–1573 Table 2
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F-FAZA scan results in patients with lymphoma
Patient no.
Gender
Age (years)
Weight (kg)
Histology
PET or PET/CT
Abnormal uptake
01 05 07 10 11
Female Female Male Female Female
44.3 64.4 25.0 66.4 52.0
75 60 95 54 89
PET/CT PET/CT PET/CT PET/CT PET/CT
No No No No No
14
Female
55.8
88
PET/CT
No
15
Male
71.3
94
PET/CT
Yes
20 21
Male Male
19.0 24.7
77 107
Follicular lymphoma Follicular lymphoma Hodgkin's disease Follicular lymphoma Diffuse large B-cell lymphoma Small lymphocytic lymphoma Diffuse large B-cell lymphoma Hodgkin's disease Hodgkin's disease
PET/CT PET/CT
Yes No
28 30 31
Female Male Male
18.2 41.2 62.8
97 86 79
PET PET PET
No No No
32
Male
56.3
72
PET
No
34
Male
32.1
83
PET/CT
35 37
Female Male
62.3 47.9
90 90
43 45
Female Male
38.3 55.0
78 98
46
Female
59.9
63
47
Male
62.8
101
50
Female
87.1
58
Hodgkin's disease Hodgkin's disease Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma T-cell lymphoma Diffuse large B-cell lymphoma Hodgkin's disease Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
Site of uptake
RUS
T/B ratio
SUVmax
Transverse colon Mediastinum
4
3.0
4.52
3
1.7
1.50
Yes
Mid-chest
1
1.2
1.07
PET PET/CT
No Yes
Right pleura
3
1.9
1.99
PET PET
No Yes
Gluteal
2
1.4
2.15
PET
No
PET
Yes
Supraclavicular
2
1.6
1.60
PET
Yes
Right pelvis
2
1.3
2.23
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
Table 3
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
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F-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 12 19 25 26
Male Female Female Male Male
70.5 49.7 57.0 72.5 80.9
97 61 71 73 90
GBM GBM GBM GBM GBM
PET/CT PET/CT PET/CT PET/CT PET/CT
Yes Yes Yes Yes Yes
4 4 4 4 2
2.8 2.7 15.6 4.4 1.9
38 40
Male Male
59.7 52.2
106 91
GBM GBM
PET PET/CT
Yes Yes
Left frontal lobe Left temporal lobe Left hemisphere Right frontal lobe Right temporal lobe Left frontal lobe Right temporal lobe
4 4
5.2 4.4
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Eur J Nucl Med Mol Imaging (2009) 36:1565–1573
Fig. 2 Increased uptake of 18FFAZA 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
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F-FAZA scan results in patients with lung cancer
Patient no.
Gender
Age (years)
Weight (kg)
Histology/site
PET or PET/CT
Abnormal uptake
16 17
Female Male
70.5 90.0
71 92
Adenocarcinoma/right lung Adenocarcinoma/left lung
PET/CT PET/CT
No Yes
22
Male
76.8
72
23 27
Female Male
49.1 78.6
64 66
29
Female
78.8
76
36
Male
80.6
93
39
Male
81.7
41
Female
42
Squamous cell carcinoma/ left lung Adenocarcinoma/right lung Squamous cell carcinoma/ right lung
PET/CT
Yes
PET/CT PET/CT
Yes Yes
PET
No
PET
No
50
Squamous cell carcinoma/ left lung Small-cell carcinoma/right lung Pancoast tumour/left lung
PET
Yes
62.1
61
Adenocarcinoma/left lung
PET/CT
Yes
Male
63.0
88
PET
Yes
44
Male
66.5
115
PET/CT
No
48 49
Female Male
62.0 59.2
53 101
Squamous cell carcinoma/ left lung Anaplastic large-cell carcinoma/right lung Adenocarcinoma/right lung Squamous cell carcinoma/ left lung
PET PET
No No
Site of uptake
RUS
T/B ratio
SUVmax
Left upper lobe Left lower lobe Left upper lobe Right lung Right upper lobe
2
1.4
1.10
2
1.3
1.29
3
2.4
1.93
3 2
2.4 2.0
1.65 0.96
3
2.4
1.49
3
3.7
0.81
2
3.1
1.50
Left upper lobe Left lower lobe Left lower lobe
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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 18FFAZA 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
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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 18 F-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 62Culabelled diacetyl-bis(N4-methylthiosemicarbazone) (62CuATSM) [26], reported high lung tumour radioactivity, with an SUV max of 2.7. 18 F-labelled 1-(2-fluoro-1[hydroxymethyl]-ethoxy)-methyl-2-nitroimidazole ( 18FFRP170) 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 18FFAZA. 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 18 F-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 progressionfree 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.
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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.
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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