Hypoxia imaging-directed radiation treatment planning.

Increasing evidence supports the role of the tumor microenvironment in modulating cancer behavior. Tissue hypoxia, an important and common condition affecting the tumor microenvironment, is well established as a resistance factor in radiotherapy. Increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behavior and promote broad resistance to therapy. These factors suggest that determining the presence or absence of tumor hypoxia is important in planning cancer therapy. Recent advances in PET hypoxia imaging, conformal radiotherapy, and imaging-directed radiotherapy treatment planning now make it possible to perform hypoxia-directed radiotherapy. We review the biological aspects of tumor hypoxia and PET imaging approaches for measuring tumor hypoxia, along with methods for conformal radiotherapy and image-guided treatment, all of which provide the underpinnings for hypoxia-directed therapy. As a case example, we review emerging data on PET imaging of hypoxia to direct radiotherapy.

[(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression.

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (>or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.

Brain SPECT used to evaluate vasospasm after subarachnoid hemorrhage: correlation with angiography and transcranial Doppler.

PURPOSE: The primary objective of this study was to correlate Tc-99m HMPAO and ethyl cysteine dimer perfusion brain SPECT imaging with angiography and transcranial Doppler (TCD) to identify vasospasm after subarachnoid hemorrhage. METHODS: A retrospective analysis of consecutive patients who had cerebral blood flow SPECT imaging for subarachnoid hemorrhage and aneurysm clipping was made. Flow velocity measurements were correlated using TCD and cerebrovascular angiography. RESULTS: Of the 129 patients were included in this study, 84 were female and 45 were male, with a mean age of 51.9 years and a median age of 51 years (range, 9 to 84 years). Eighty-nine patients had brain SPECT evidence of hypoperfusion. Concordance was found between SPECT and TCD with vasospasm in 57 of 89 (64%) patients and nonconcordance was evident in 32 patients (36%). Eleven patients who had concordance between SPECT and TCD had nonconcordant results of angiography for vasospasm. CONCLUSIONS: These findings suggest that all three methods are complementary to each other in the evaluation of patients with vasospasm after subarachnoid hemorrhage. Concordance of 64% between SPECT and TCD is acceptable and explicable by the differences in technique and measurement of cerebral blood flow compared with vascular narrowing, respectively.

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Review of 6-month mortality following low-probability lung scans.

BACKGROUND: Ventilation perfusion lung scanning is widely used as a diagnostic method for evaluating patients suspected of having pulmonary embolism (PE). While lung scan interpretation is traditionally performed in terms of probability of PE (usually low, moderate or intermediate, and high), in recent years concern has been raised that the term low probability may be misleading because adverse and even fatal sequelae of PE occasionally occur in such patients. To assess these concerns, a review of mortality in a large series of patients following low-probability lung scans was performed. OBJECTIVE: To determine the 6-month mortality in a consecutive series of patients following low-probability ventilation perfusion (V/Q) lung scans. METHODS: Records of all patients who had low-probability V/Q scans during a 9-year period (1987-1995) were reviewed. Causes of mortality for those patients who died during the 6-month period after the index scan were established from patients' charts, autopsy reports, and computer record data. RESULTS: Of the total 536 evaluable patients, 83 (15%) died within 6 months of the date of the lung scan; 73 (88%) died while inpatients at the Seattle Veterans Affairs Medical Center, Seattle, Wash, and the other 10 (12%) died at other facilities or at home. Pulmonary embolism was not reported as a suspected or probable contributing factor in any of the 83 deaths. Sixty-three patients (76%) who died had a diagnosis of either cancer (n = 32) or advanced cardiovascular disease (n = 31) at the time of their lung scans. Twenty-six patients (31%) underwent autopsies, and PE was not identified on examination of the lungs in any of them. Of the 27 patients who died within 1 month of the scan date, 17 (63%) underwent autopsies. CONCLUSION: Review of data from all patients with low-probability V/Q scans and a follow-up of 6 months showed no documentation to attribute any deaths to PE.