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First published online July 19, 2006
British Journal of Radiology (2006) 79, 791-798
© 2006 British Institute of Radiology
doi: 10.1259/bjr/17904358
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Review article

Hypoxia in head and neck cancer

A Y Isa, MBChB, MRCS, M Phil 1 T H Ward, PhD 2 C M L West, BA, PhD 3 N J Slevin, MBChB, FRCP, FRCR.BW 4 and J J Homer, MD, FRCS (ORL-HNS) 5

1 Department of Surgery, Christie Hospital, Manchester, 2 Drug Development Group, Paterson Institute for Cancer Research, Manchester, 3 Academic Department of Radiation Oncology, University of Manchester, Manchester, 4 Department of Clinical Oncology, Christie Hospital, Manchester, 5 Departments of Surgery, Christie Hospital and University Department of ORL-HNS, Manchester Royal Infirmary, Manchester, UK

Correspondence: Mr J J Homer, University Department of Otolaryngology-Head and Neck Surgery, Manchester Royal Infirmary, Oxford Road, Manchester M13 9DL, UK.


   Abstract
Top
 Abstract
Introduction
 The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 
A high level of hypoxia in solid tumours is an adverse prognostic factor for the poor outcome of cancer patients following treatment. This review describes the status of research into finding a practical method for measuring hypoxia and treating hypoxic tumours. The application of such methodology would enable the selection of head and neck cancer treatment based on an individual's tumour oxygenation status. This individualization would include the selection not only of surgery or radiotherapy, but also of novel hypoxia-modification strategies.


   Introduction
Top
 Abstract
 Introduction
The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 
Hypoxia, the inadequate supply of blood-borne oxygen, has been linked with a poor tumour response to radiotherapy [1–4]. This resistance relates, in part, to the radiobiological effects of hypoxia. However, hypoxia is also a marker of an aggressive tumour phenotype and is associated with a poor outcome following surgery [5, 6]. Furthermore, hypoxia is implicated in the resistance of tumours to some chemotherapeutic agents [7]. This review discusses the biology of tumour hypoxia, methods for measuring tumour hypoxia, possible clinical applications of hypoxia measurements and potential hypoxia modification approaches for patients with head and neck cancer.


   The biology of tumour hypoxia
Top
 Abstract
 Introduction
 The biology of tumour...
Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 
Tumour cells require a host vasculature for their supply of nutrients and oxygen, but oxygen cannot diffuse further than around 150 µm through tissues. As tumour growth outstrips its vasculature, the cells become hypoxic [8]. This hypoxia, termed chronic or diffusion-limited hypoxia, occurs adjacent to areas of necrosis. Tumour hypoxia also arises from the transient or intermittent occlusion of tumour blood vessels, called acute or perfusion-limited hypoxia. Although the mechanisms behind the development of acute hypoxia are unknown, it may arise from the blocking of vessels by circulating blood and tumour cells, blood vessel collapse from high tumour interstitial pressure, and/or the interruption of tumour blood flow. All these factors could occur because of the chaotic, disorganized and fragile nature of tumour compared with normal tissue vasculature [9, 10].

Thomlinson and Gray first proposed the existence of hypoxia in human tumours in 1955 [11] and confirmed the radioresistance of hypoxic mammalian cells, which was described in 1936 by Mottram [12]. Thomlinson and Gray suggested that the presence of quiescent but viable hypoxic cells, capable of re-oxygenation during fractionated radiotherapy, would limit the success of treatment. This suggestion spurred research into finding methods for measuring tumour hypoxia and for overcoming hypoxic cells in patients undergoing radiotherapy. It is only in the last decade, however, that hypoxia has emerged as a key factor in driving malignant progression. Hypoxia is involved in the transcriptional regulation of a number of genes. Hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) and HIF-2{alpha} are transcription factors that mediate cell responses to hypoxia. Cells express HIF-1{alpha} continuously, but the protein degrades rapidly under normoxic conditions. In hypoxia, the protein is stabilized and induces the transcription of a number of genes including those involved in angiogenesis, glycolysis, pH control and oxygen delivery. HIF-1{alpha} transcribed genes include the key angiogenic growth factor, vascular endothelial growth factor (VEGF) [13], as well as glucose transporter 1 (Glut-1) [14] and the pH regulator, carbonic anhydrase IX (CAIX) [15]. Thus, cellular response to hypoxia strives to prevent cell death. HIF-1{alpha} up-regulation occurs within 2 min of hypoxia, accumulating rapidly over 30 min to peak after another 30 min [16].


   Clinical importance of hypoxia
Top
 Abstract
 Introduction
 The biology of tumour...
 Clinical importance of hypoxia
Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 
The biological effect of radiation depends on the degree of oxygenation, and hypoxic cells are approximately three-fold more resistant than well-oxygenated cells. This oxygen effect is due to the interaction between oxygen and the free radicals produced when radiation is absorbed in tissues. Radiation absorbed in tissues produces highly reactive, short-lived free radicals, which produce double strand breaks in DNA leading to cell death. The oxygen increases the damage produced by radiation by increasing the lifetime of the free radicals. Due to the short life-span of the free radicals, oxygen needs to be present at the time of irradiation to be effective [17]. Studies showed poorer locoregional control and survival in patients with hypoxic compared with oxygenated head and neck squamous cell cancers treated with radiation [1–4].

There is evidence that hypoxia limits the effectiveness of not only radiotherapy but also surgery. In studies measuring tumour oxygenation using polarographic oxygen microelectrodes, tumours treated with primary surgery with or without radiation had a poor outcome [5, 6]. Hockel et al found the median partial pressure of oxygen (pO2) to be the strongest independent predictor of overall and disease-free survival in patients with locally-advanced uterine cervical cancer irrespective of treatment modality. Similar findings reported with high-grade non-metastatic soft tissue sarcomas [6] indicate the involvement of factors other than hypoxia-mediated radioresistance. There is evidence that hypoxia enhances genetic instability in tumour cells and selects for tumour cell populations with diminished apoptotic potential, and increased aggressiveness and metastatic potential [17–19].

Hypoxia has also been implicated in the resistance of tumours to some chemotherapeutic agents, including those used in the treatment of head and neck cancers [7]. Hypoxic cells are resistant to 5-fluorouracil, doxorubicin, bleomycin and cisplatin [20–23]. Although the mechanisms behind this drug resistance are not understood, reduced cellular proliferation, low pH and hypoxia-induced alterations in gene expression may play a role.


   Measuring hypoxia
Top
 Abstract
 Introduction
 The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 
Various methods are under development for measuring tumour hypoxia in cancer patients. There is a need for a method that is practical, fast and reliable, i.e. suitable for routine clinical application. Although intratumour variability in oxygenation is a potential confounding factor affecting many of the measurement strategies, tumour-to-tumour variability is greater [17]. The ability to differentiate between necrotic and hypoxic areas is also important, but not possible with all techniques. Whilst the ultimate result of hypoxia is necrosis (and therefore necrotic cells might be a measure of the process of hypoxia), it is the measurement of hypoxic cells that remain viable that are of the greatest clinical importance.

Oxygen microelectrodes
The current resurgence of interest in tumour hypoxia stems from data obtained during the 1990s using computerized Eppendorf oxygen microelectrodes. Advantages of Eppendorf over older style electrodes were the use of fine needles to minimize tissue trauma, an automatic stepper motor to enable rapid movement through tissue and to avoid tissue compression artefacts and computerization to enable the quick collection of multiple measurements. The electrodes are used with or without image guidance, depending on the location and size of the tumour. Le et al showed that median pO2 readings from advanced head and neck cancer nodal metastases were significantly lower than normal subcutaneous tissue (14.6 mmHg vs 51.2 mmHg; p<0.001) and in each patient, median tumour metastases pO2 was consistently lower than that of normal subcutaneous tissue. 40% of the study group had median pO2 measurements of less than 10 mmHg [24]. Nordsmark et al [3] found in their study of pre-treatment oxygenation in neck metastasis of advanced squamous cell carcinoma of the head and neck that the fraction of pO2<2.5 mmHg was significant as a continuous variable of local failure following radiotherapy, but median pO2 was not. Another study of head and neck squamous cell carcinoma (HNSCC) treated with chemoradiotherapy/radiotherapy showed that the hypoxic subvolume defined as the percentage of tumour multiplied by percentage of pO2-values below 5 mmHg were significant in multivariate analysis for poorer overall survival where no correlation was found with median pO2 [18]. The approach, however, is limited to tumours that are accessible. Also, oxygen electrodes cannot differentiate viable hypoxic regions from necrotic areas [25, 26].

Comet assay
The comet assay uses individual tumour cells dissociated from needle biopsies. It is a sensitive method of measuring DNA strand breaks in tumour cells after single doses of 3.5–10 Gy. The approach is based on the fact that ionizing radiation produces around three-fold more damage in well-oxygenated compared with hypoxic cells (i.e. it measures radiobiologically hypoxic cells) [27, 28]. The comet assay was compared with the oxygen microelectrode system in a group of patients with heterogeneous advanced tumours (including non-HNSCC). Aquino-Parsons et al found a correlation between hypoxic fraction measured by comet assay and percentage of pO2 values <5 mmHg measured by the oxygen microelectrode (r2 = 0.46, p<0.001). In their study, tumours defined as hypoxic with a median pO2<10 mmHg were found to have >20% radiobiologically hypoxic cells as measured by the comet assay [28]. Another study compared the two methods in node positive Stage III–IV HNSCC. The majority had Stage IV disease and were randomized to cisplatin-based induction chemotherapy followed by concurrent chemoradiotherapy with or without tirapazamine. A weak but statistically significant negative correlation between oxygen microelectrode median pO2 and 1 min median tail moment as a measure of DNA damage post-irradiation from the comet assay was found (r2 = 0.08, p = 0.05). There was a significant correlation between response and comet median tail moment (p = 0.001); however, no correlation was found between response and median pO2 readings [24]. The lack of correlation between median pO2 and response is not unexpected as Nordsmark et al had described this in an earlier study [3]. The use of median pO2 instead of percentage pO2<5 mmHg may also explain the negative correlation between the oxygen microelectrode and the comet assay.

The advantage of the comet assay lies in its ability to measure radiobiologically hypoxic cells only and not necrosis. Radiation doses in excess of 3.5 Gy are required to produce sufficient DNA damage to distinguish a hypoxic subpopulation, thus limiting its application to patients receiving larger fractions or doses. Contamination of the fine needle aspirate sample by circulating white blood cells (which are unirradiated) could falsely reduce the median tail moment making the tumour seem more hypoxic [28, 29].

Using nitroimidazoles as hypoxic markers
Nitroimidazoles are nitro aromatic compounds that bind to hypoxic cells. Nitroimidazoles diffuse easily into hypoxic cells due to their high solubility and low metabolism [27]. A non-therapeutic dose of a nitroimidazole is administered, systemically prior to biopsy or resection of a tumour, and hypoxic cells in histological sections can be identified using immunohistochemistry (IHC), flow cytometry and immunofluorescence. Nitroimidazoles used as hypoxic markers include misonidazole, pimonidazole, etanidazole, EF5 and nitroimidazole-theophylline [17, 30]. An advantage of the approach is its applicability to tumours inaccessible to oxygen electrodes. However, a biopsy might not be representative of the heterogeneity of hypoxia within a whole tumour. Although no relationship was found between pimonidazole binding and oxygen electrode data in carcinoma of the cervix [31], a study in head and neck cancer showed that high pimonidazole binding did predict adverse treatment outcome. Locoregional tumour control was statistically significantly lower for patients who had hypoxic tumours with 2-year control rates of 48% vs 87% for tumours with high and low pimonidazole binding levels, respectively [32]. This finding raises the possibility that measurements of pimonidazole binding in head and neck cancer might be useful as a selection tool for hypoxia-modifying treatments. However, pimonidazole staining in highly differentiated or keratanized tumour tissue has been described. The question as to whether these areas are hypoxic has been raised. This is especially pertinent in head and neck cancers that have a considerable amount of keratinization as pimonidazole staining of keratinized but non-hypoxic areas would lead to an overestimation of the level of hypoxia. Janssen et al found in 25% of their head and neck cancer series up to 30% of staining was in well-differentiated areas [33]. Further investigation is required.

Measuring endogenous markers of hypoxia
Hypoxia-inducible proteins are under investigation as potential endogenous markers of hypoxia. The expression of HIF and the proteins it regulates transcriptionally can be measured using IHC [34]. The advantage of the approach for routine clinical use is that, as for nitroimidazole probes, only a biopsy is required. Disadvantages are that a single biopsy might not be representative of a whole tumour and that the proteins investigated can be upregulated by factors other than hypoxia, i.e. they are not hypoxia specific. Potential endogenous markers of hypoxia investigated include HIF-1{alpha}, HIF-2{alpha}, Glut-1 and CAIX. Strong HIF-1{alpha} expression was associated with a significantly poorer outcome following radiotherapy in oropharyngeal tumours expressing HIF-1{alpha} [35]. High HIF-1{alpha} and HIF-2{alpha} expression was associated with poor outcome in patients with advanced squamous cell carcinoma of the head and neck treated with concurrent carboplatin chemoradiotherapy [36]. Complete response was lower in tumours expressing HIF-1{alpha} and/or HIF-2{alpha} 49% vs 86% (p = 0.004) and high expression of HIF-1{alpha} and HIF-2{alpha} was significantly associated with poor local relapse-free survival (p = 0.003 and p = 0.003, respectively) and overall survival (p = 0.05 and p = 0.001, respectively) in univariate analysis. HIF-2{alpha} over expression was also an adverse prognostic factor for locoregional control (p = 0.002) and overall survival (p = 0.0004) in head and neck cancers treated with accelerated radiotherapy [37]. However, the expression of HIF-1{alpha} in surgically treated head and neck squamous cell carcinoma was associated with improved disease-free survival (p = 0.016) and overall survival (p = 0.027) where no difference in outcome was seen with HIF-2{alpha} expression [34]. A more recent study of T1/2 squamous cell carcinomas of the floor of mouth confirmed the positive prognostic effect of HIF-1{alpha} expression in surgically treated patients. In this series of 85 patients, HIF-1{alpha} expression was associated with a significantly improved 5-year survival rate (p<0.01) and a significantly increased disease-free period (p = 0.01) [38]. It remains to be established whether the importance of the expression a hypoxia-inducible marker that is upregulated by factors other than hypoxia will vary with disease stage, but clearly this is an area that needs further study.

Glut-1 is a ubiquitously expressed facilitative glucose transporter that is over-expressed in a number of tumours [39]. Although Glut-1 is upregulated by a variety of agents and conditions, it has potential as an intrinsic marker of hypoxia because of dual control of expression in hypoxic conditions via HIF-1 and reduced oxidative phosphorylation [14]. Its expression is heterogeneous in cell cytoplasm and membrane, and over-expression has been shown in tumours including those of the breast [40], lung [41], thyroid [42], cervix [39], hypopharynx [43] and oral cavity [44]. Glut-1 staining tends to localize in necrotic and perinecrotic areas of tumours [39]. Over expression of Glut-1 was associated with a poor prognosis in oral squamous cell carcinoma [44, 45] and hypopharyngeal carcinoma [43]. For example, survival times were 138 months and 60 months for patients with surgically treated oral squamous cell carcinoma expressing low versus high levels of Glut-1, respectively [44]. Recent experiments on human tumour-derived xenografts revealed that the chemosensitivity of certain alkylating agents may be influenced by Glut-1 expression [46]. However, there is only a very weak [39] or no [47] relationship between tumour Glut-1 expression and oxygen variables (pO2, hypoxic fractions 2.5 and 5). The latter, along with the lack of prognostic significance of Glut-1 expression in multivariate analysis, has raised questions on the suitability of Glut-1 as an endogenous hypoxia marker [47].

CAIX is a transmembrane glycoprotein that is induced by hypoxia via the HIF-1 pathway and may be a useful endogenous marker of hypoxia [15]. Expression of CAIX in hypoxic tumours is localized to perinecrotic regions and is thought to confer a survival advantage by maintaining intracellular pH [15]. CAIX expression correlated with tumour oxygenation status measured using oxygen electrodes in cervical squamous cell carcinomas and is associated with poor outcome following radiotherapy [48]. CAIX expression is associated with poor complete response rate (40% vs 70%, p = 0.02) to chemoradiotherapy in advanced squamous head and neck cancer [49]. Interestingly, the co-expression of HIF-1{alpha} and CAIX were associated with a poorer progression-free survival (p = 0.04) in chemoradiated locally advanced nasopharyngeal cancer than the expression of either marker alone [50]. The combined expression of CAIX and Glut-1 in HNSCC treated radiotherapy with or without chemotherapy was also associated with poorer local control (p = 0.02) and disease-free survival (p = 0.04) where expression of either marker alone was not significantly correlated with outcome [51].

More recently, interest has grown in osteopontin – an extracellular matrix protein involved with tumour cell invasion, migration, angiogenesis and tumour growth [52, 53]. Osteopontin is secreted in plasma making it an attractive, easy method of assessing hypoxia. Plasma osteopontin levels were inversely correlated with pO2 (p = 0.003, r = –0.42) in HNSCC and osteopontin was an independent predictor for freedom from relapse and survival on multivariate analysis [54]. The prognostic significance of osteopontin in HNSCC treated by radiotherapy was supported by Overgaard et al [55]. Moreover, the prognosis of patients with high levels of osteopontin was improved by addition of hypoxia modifier nimorazole. Locoregional failure (RR 0.19 [95% CI 0.08–0.44]) and disease specific mortality (RR 0.25, 95% CI 0.11–0.59) was more frequent in patients with high concentration of osteopontin assigned placebo than those assigned nimorazole [55].

Hypoxic regions within solid tumours will be not only oxygen deficient, but also acidic and nutrient depleted. Recent studies indicating that glucose concentration [56] and pH [57] affect the expression of endogenous markers of hypoxia raise concern over the generalized use of these proteins or genes as hypoxic markers. In vitro experiments using FADU human pharyngeal carcinoma and HT1080 human fibrosarcoma cells showed a lack of hypoxic HIF-1{alpha} accumulation in glucose-depleted conditions. Serum-depleted conditions also caused decreased hypoxic HIF-1{alpha} accumulation in FADU cells despite the presence of glucose [56]. Even though Vordermark et al [56] showed no effect of pH on HIF-1{alpha} expression, Sorensen et al [57] found that the expression of CA9, GLUT1 and Osteopontin (OPN) genes were inhibited in hypoxia when extracellular pH was reduced to 6.3. As CA9 and GLUT1 are HIF-1 regulated genes it is likely that HIF-1 will be affected by pH as well. A possible explanation for the findings of Vordermark et al may be that the lowest pH level of 6.7 was not acidic enough to show any inhibitory effect. The time course and the levels to which the genes were upregulated were different, as was the oxygen concentration at which upregulation was maximal, e.g. after 24 h exposure CA9 upregulation was maximal at 1% oxygen whereas GLUT1 and OPN were maximal at 0.01% and 0% oxygen, respectively [57]. More work is required to reveal any other factors that may effect these proteins or genes that have until now been loosely termed endogenous markers of hypoxia. Perhaps the term "markers of poor prognosis" may be more apt. It may be that instead of utilizing a single protein, tumours should be tested for multiple markers to create a hypoxia-associated molecular profile.

Non-invasive imaging
2-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) utilizes the concept that most tumours exhibit accelerated glycolysis allowing 18F-labelled FDG to be trapped in tissues with a higher metabolic rate than normal tissues [58]. There are several studies with contradictory findings with regards the correlation of Glut-1 expression and 18F-FDG uptake in tumours [59–62]. Most studies compared standardized uptake ratios or values from pre-operative 18F-FDG PET scans and compared them with immunohistochemical Glut-1 expression from a section of the tumour or a biopsy specimen. Interestingly, a recent article based on a rat tumour model showed a good correlation between 18F-FDG uptake and Glut-1 expression (r = 0.829, p<0.001) at a micro-regional level [60]. Even so, the ability of 18F-FDG to detect tumour hypoxia is questionable [63, 64]. The imaging of radiolabelled nitroimidazoles by single-photon emission computer tomography (SPECT) and PET as a non-invasive measure of hypoxia is also being studied, amongst them 18F-fluoromisonidazole (18FMISO) [63], 18F-fluoroerythronitroimidazole (18F-FETNIM) [65], 18F-fluoroetanidazole (18F-FETA) [66], and 18F-EF3 [67]. Metal labelled hypoxia markers are also currently being developed, e.g. Cu ATSM [68]. Preliminary clinical testing of some of these markers has been promising with small series indicating a prediction of radiotherapy outcome [65, 69]. Advantages of the PET based approach include the ability to assess hypoxia of the whole tumour using a non-invasive technique that evaluates viable regions within the tumour. Deep lesions that are otherwise inaccessible to the microelectrodes can be studied and sequential scans can indicate response to treatment. A disadvantage is the limited spatial resolution.

Cross sectional imaging methods are also being studied, in particular MRI. The methods are not hypoxia specific, but the wide availability of MRI is an advantage of the approach. Dynamic contrast-enhanced MRI has been the most widely studied method. The method yields parameters that reflect, amongst other parameters, tumour perfusion and vascularity. There is some evidence that the approach can yield data that reflect tumour oxygenation [70], and predict radiotherapy outcome in patients with carcinoma of the cervix and advanced head and neck cancer [71, 72].


   Hypoxia modification strategies
Top
 Abstract
 Introduction
 The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
Hypoxia specific cytotoxins
 References
 
There are a number of approaches under investigation to improve the oxygenation status of tumours. Oxygen delivery to a tumour can be raised by increasing the oxygen content of inspired air or raising haemoglobin levels. There are also hypoxia specific cytotoxins such as bioreductive drugs. For tumours treated with radiation, hypoxic cell radiosensitizers and radiotherapy modulation strategies are being developed.

Increasing oxygen delivery
One of the earliest hypoxia modification strategies studied was hyperbaric oxygen. Although breathing oxygen during radiotherapy was used to some success in the past, delivery was complex and patient tolerance poor. Carbogen (2–5% carbon dioxide and oxygen) was suggested as an alternative to pure oxygen because of it causing vasodilation, an increase in respiratory drive and a right shift in the oxygen-haemoglobin dissociation. Patients breathe carbogen through a face mask during their radiotherapy. Accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) is being investigated in patients with head and neck cancer. The accelerated radiotherapy targets rapidly proliferating tumour cells, the carbogen maximizing arterial pO2 and nicotinamide is a vasodilator that aims to minimize diffusion-limited hypoxia. The radiosensitizing effect of ARCON can also be expected in normal tissue hence the need for reduced doses to the spinal cord and laryngeal cartilage [73, 74] and the importance of its selective use based perhaps on hypoxia measurement. So far, results with ARCON in clinical trials in squamous cell carcinoma of the head and neck have been mixed [74, 75]. How much additional benefit with ARCON is due to hypoxia reduction as opposed to reduction in tumour clonogenic repopulation by accelerated fractionated radiotherapy has not been ascertained.

Raising haemoglobin levels
Anaemia is associated with a poor outcome following chemoradiotherapy and radiotherapy [18, 76, 77]. The detrimental effect of anaemia on radiotherapy outcome has led to the routine use of blood transfusions prior to radiotherapy in patients with low haemoglobin levels. An alternative approach under investigation is the use of erythropoietin. Erythropoietin increases red cell production and theoretically reduces tumour hypoxia. In a retrospective study of patients with oropharyngeal cancer treated with chemoradiotherapy prior to surgical resection, Glaser et al found that a low pre-operative haemoglobin level was an independent adverse prognostic factor for locoregional control and survival [76]. This was reversed with the use of recombinant human erythropoietin during chemoradiotherapy. However, a recent double-blind, placebo-controlled randomized trial using erythropoietin in head and neck cancer patients undergoing radiotherapy did not show any improvement in treatment outcome and actually suggested poorer locoregional progression-free survival [78]. Further carefully controlled trails are required to study this more closely.


   Hypoxia specific cytotoxins
Top
 Abstract
 Introduction
 The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
References
 
Bioreductive drugs are reduced under hypoxia or by reducing enzymes to cytotoxic metabolites [79]. Quinone (e.g. mitomycin C, porfiromycin), nitroimidazole (e.g. RSU-1069) and N-oxide (e.g. tirapazamine) compounds can be bioreduced to cytotoxic species. Although mitomycin C was used to treat head and neck cancer patients before it was known to be a bioreductive agent, it is not hypoxia selective and there is little differential cell killing between oxygenated and hypoxic cells. Of the new agents developed for their preferential toxicity toward hypoxic cells, tirapazamine is probably of most interest. Tirapazamine exhibits selective cytotoxicity for hypoxic cells. It is reduced in hypoxia to a highly reactive radical, which is capable of causing single and double strand DNA breaks. In normoxia this radical is back oxidized to the inert parent compound. This cycle is thought to confer hypoxic selectivity [80]. Tirapazamine can be given with other cytotoxic agents or with radiotherapy. A phase I trial of fractionated radiotherapy with concomitant tirapazamine and cisplatin in advanced oropharyngeal cancer, found dose limiting toxicity in the form of febrile neutropenia. This was overcome by omitting tirapazamine in weeks 5 and 6. Measurement of hypoxia by 18F-misonidazole PET scanning revealed a decrease in tumour hypoxia following treatment [81]. A recent randomized phase II trial comparing tirapazamine, cisplatin and radiation versus fluorouracil, cisplatin and radiation in 120 stage III and IV HNSCC patients found a trend in favour of the tirapazamine arm for both locoregional control (84% vs 66%) and failure-free survival (55% vs 44%). This became statistically significant for locoregional control following adjustment for known prognostic factors [82].

Gene therapy strategies are also under investigation to target hypoxic cells in solid tumours. These include using anaerobic bacteria, e.g. Clostridium Spp as a vector to deliver genetic material preferentially to hypoxic tissue at sufficient levels to cause a therapeutic effect [79]. HIF-1{alpha} downregulation by intratumoural delivery of antisense HIF-1{alpha} plasmid showed promising results [83].

Hypoxic cell radiosensitizers
As discussed above, nitroimidazoles can diffuse into hypoxic cells due to their high solubility and low metabolism. The radiosensitizing effects of these compounds are related to their electron affinity, mimicking the oxygen effect, increasing DNA damage and restoring radiosensitivity. The use of first generation nitroimidazoles (e.g. misonidazole) was limited due to intolerable side effects including irreversible peripheral neuropathy. However, nimorazole, a 5-nitroimidazole derivative, has fewer side effects [84]. A phase III trial in Denmark showed significantly increased locoregional control in supraglottic and pharyngeal tumours treated with nimorazole and conventional radiotherapy [77].

Improving the delivery of radiotherapy
Radiotherapy can be modulated to deliver more radiation to hypoxic tumours. Intensity-modulated-radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT) [85] enables small irregular volumes to be "painted" with radiotherapy. With better methods of detecting hypoxic microregions in the future, possibly with PET and SPECT, it may be possible to select hypoxic regions within tumour for treatment with higher radiation doses using these techniques.

The future: individualizing treatment according to hypoxic status
The choice of treatment for patients with head and neck cancer is often a matter of clinician and centre preference. There is an unmet need for biological parameters to individualize treatments. The various ways of measuring hypoxia provide potentially promising ways of predicting response to radiotherapy. This may allow clinicians to choose primary surgery or (chemo)radiotherapy on a scientific, individualized basis, rather than by protocol and acumen. This individualization of treatment has potential to improve patient management in two ways. First, a decrease in radiation failures would reduce the need for salvage surgery, which is associated with greater surgical morbidity than primary surgery [86]. Second, there would be a more appropriate selection of patients for organ preserving chemoradiotherapy. Furthermore, there are number of specific hypoxia modification strategies that can be applied to patients on an individualized basis.

Progress in the development of a tool for measuring tumour hypoxia should enable the future informed clinical choice between primary (chemo)radiotherapy, (chemo)radiotherapy with hypoxia modification strategies or radical surgery for locally advanced tumours.

This work was supported by the Wolfson Foundation, the Christie Hospital Endowment Fund and the National Translational Cancer Research Network.

Received for publication July 21, 2005. Revision received April 19, 2006. Accepted for publication May 22, 2006.


   References
Top
 Abstract
 Introduction
 The biology of tumour...
 Clinical importance of hypoxia
 Measuring hypoxia
 Hypoxia modification strategies
 Hypoxia specific cytotoxins
 References
 

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