Hypoxia and Glucose Metabolism in Malignant Tumors

Rajendran, Joseph G.; Mankoff, David A.; O’Sullivan, Finbarr; Peterson, Lanell M.; Schwartz, David L.; Conrad, Ernest U.; Spence, Alexander M.; Muzi, Mark; Farwell, D. Gregory; Krohn, Kenneth A.

doi:10.1158/1078-0432.ccr-0688-3

Cited by 364 publications

(240 citation statements)

References 39 publications

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“…The other 7 patients exhibited variable degrees of mismatch between the location of the most intense areas within the tumor between FMISO1 and FMISO2. These findings suggest that additional work is required to identify the underlying causes of changes in intratumor radiotracer distribution before 18 F-FMISO PET images can be used as the basis of hypoxia-targeting IMRT planning. Only then, could 18 F-FMISO PET/CT-guided dose painting IMRT be used to dose escalate the hypoxic gross tumor volume within the tumor volume (without compromising normal tissue sparing) and thus reducing gross tumor volume radiation resistance due to hypoxia and improving local control.…”

Section: Resultsmentioning

confidence: 99%

“…Coronal view shows one of the BBs used to assist in registration (BB diameter, 1 mm). Maximal standardized uptake value (SUV max ) for tumor vs. hypoxic volume (using tumor/ blood threshold of ≥1.2) for (a) 18 F-fluoromisonidazole (FMISO)1 and (b) FMISO2 studies. Table 2 Tumor GTV, maximal tumor SUV, maximal blood SUV scan time after injection, blood time after injection, FHVs, and correlation coefficients, R, between corresponding voxel SUVs within TV of aligned FMISO1 FMISO2 TVs …”

Section: Resultsmentioning

confidence: 99%

“…One potential strategy to improve the effectiveness of RT is to selectively boost the hypoxic volume within the tumor using intensity-modulated RT (IMRT) (28,29). In this approach, IMRT is used to increase the dose to the "hypoxic tumor volume," a subvolume defined within the conventional gross tumor volume, as defined by the tumor hypoxia images (e.g., 18 F-FMISO-PET). However, such a strategy is predicated on the time invariance of tumor hypoxia as detected by PET tracers.…”

Section: Introductionmentioning

confidence: 99%

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Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

Nehmeh

Lee

Schröder

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

192

130

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Purpose-Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. 18 F-fluoromisonidazole ( 18 F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of 18 F-FMISO intratumor distribution using two pretreatment PET scans.Methods and Materials-We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an 18 Ffluorodeoxyglucose study, followed by two 18 F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio ≥1.2. The 18 F-FMISO tracer distributions from the two 18 F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the 18 F-FMISO intensities of the corresponding spatial voxels was derived.Results-A voxel-by-voxel analysis of the 18 F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%.Conclusion-Variability in spatial uptake can occur between repeat 18 F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of 18 F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before singletime-point 18 F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

Nehmeh

Lee

Schröder

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

192

130

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“…4). However, a direct correlation between high glucose uptake and hypoxic regions was not observed [49,50]. This may result from the fact that only highly hypoxic regions, though not necrotic, are detected with FMISO, so areas where the oxygen concentration is nonetheless sufficiently low for stablization of HIF-α may not be identified.…”

Section: Clinical Significance Of Hypoxia Hif and Hif Downstream Genmentioning

confidence: 99%

Hypoxia and cancer

2007

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A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.

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“…Since these exclusions, our multidisciplinary team has met to ensure that subsequent patients who participate in this feasibility study all have full blood profiles and that care was taken to ensure that the blood was not coagulated. Significant 18 F-FMISO uptake has been reported by Rajendran et al (23,(42)(43)(44) to be at tumor/blood (T/B) ratio of 1.2-1.4. In the absence of a reference standard threshold value to define hypoxia, our desire was to select a single threshold value for demarcation of the GTV h to conform to uniform planning parameters.…”

Section: Introductionmentioning

confidence: 97%

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

Lee

Mechalakos

Nehmeh

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

209

157

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Purpose-Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV h ) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV h increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ( 18 F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients.Methods and Materials-18 F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18 F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18 F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate 18 F-FMISO PET/CT-guided IMRT plans.Results-The heterogeneous distribution of 18 F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18 F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV h and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV h for 2 patients and were successful in 1, with normal tissue sparing. Conclusion-It was feasible to dose escalate the GTV h to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.

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Hypoxia and Glucose Metabolism in Malignant Tumors

Cited by 364 publications

References 39 publications

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

Reproducibility of Intratumor Distribution of 18F-Fluoromisonidazole in Head and Neck Cancer

Hypoxia and cancer

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

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