Tumor pO2 Research Articles

The Effects of Efaproxyn™ (Efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy-Mediated Inhibition of Tumor Growth in Mice

Efaproxiral, an allosteric modifier of hemoglobin, reduces hemoglobin-oxygen binding affinity, facilitating oxygen release from hemoglobin, which is likely to increase tissue pO(2). The purpose of this study was to determine the effect of efaproxiral on tumor oxygenation and growth inhibition of RIF-1 tumors that received X radiation (4 Gy) plus oxygen breathing compared to radiation plus oxygen plus efaproxiral daily for 5 days. Two lithium phthalocyanine (LiPc) deposits were implanted in RIF-1 tumors in C3H mice for tumor pO(2) measurements using EPR oximetry. Efaproxiral significantly increased tumor oxygenation by 8.4 to 43.4 mmHg within 5 days, with maximum increases at 22-31 min after treatment. Oxygen breathing alone did not affect tumor pO(2). Radiation plus oxygen plus efaproxiral produced tumor growth inhibition throughout the treatment duration, and inhibition was significantly different from radiation plus oxygen from day 3 to day 5. The results of this study provide unambiguous quantitative information on the effectiveness of efaproxiral to consistently and reproducibly increase tumor oxygenation over the course of 5 days of treatment, modeling the clinical use of efaproxiral. Also, based on the tumor growth inhibition, the study shows the efaproxiral-enhanced tumor oxygenation was radiobiologically significant. This is the first study to demonstrate the ability of efaproxiral to increase tumor oxygenation and to increase the tumor growth inhibition of radiotherapy over 5 days of treatment.

Differential risk assessments from five hypoxia specific assays: The basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients

Purpose Hypoxia adversely relates with prognosis in human tumours. Five hypoxia specific predictive marker assays were compared and correlated with definitive radiotherapy. Patients and methods Sixty-seven patients with advanced head and neck carcinomas were studied for pre-treatment plasma osteopontin measured by ELISA, tumour oxygenation status using pO 2 needle electrodes and tumour osteopontin, hypoxia inducible factor 1α (HIF-1α) and carboxyanhydrase 9 (CA9) by immunohistochemistry. The primary treatment was radiotherapy and the hypoxic radiosensitizer nimorazole. Loco-regional tumour control was evaluated at 5 years. Results All five markers showed inter-tumour variability. Inter-marker correlations were inconsistent. Only plasma osteopontin inversely correlated with median tumour pO 2, ( p = 0.02, r = 0.28) and CA9 correlated with HIF-1α ( p < 0.01, r = 0.45). In Kaplan–Meier analysis high plasma osteopontin, high HIF-1α and high proportion of tumour pO 2 ⩽ 2.5 mm Hg (HP 2.5) related significantly with poorer loco-regional control, whereas CA9 and tumour osteopontin failed to predict loco-regional control in this set dataset. When analyzing Hb, stage, and the five markers by competing risks HP 2.5 was the strongest variable to predict for loco-regional tumour control. Conclusion There was diversity and lack of correlation among five different hypoxia assays within individual tumours. High plasma osteopontin, high HIF-1α and high proportion of tumour pO 2 ⩽ 2.5 mm Hg (HP 2.5) related significantly with poorer loco-regional control, whereas CA9 and tumour OPN failed to predict local control.

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The presence of hypoxic tumor cells is critical in cancer therapy. To identify these cells, tissue pO2 can be directly measured. A feature of OxyLite pO2 system is: this allows continuous measurements at a fixed point. It has been shown, however, that tumor pO2 fluctuates substantially in continuous measurements. In those studies, various anesthetics were given by ip injection. We questioned whether those instabilities in readings were related to the type of anesthesia, and tested isoflurane, a gas anesthesia given throughout test period, in continuous measurements.

Preclinical safety and antitumor efficacy of insulin combined with irradiation

Background and purpose We have previously reported that insulin significantly enhances tumor oxygenation ( pO 2) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials. Material and methods Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO 2 (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose–response study on mice bearing FSaII fibrosarcoma. Results The effect on regrowth delay was directly correlated with the effect on the tumor pO 2, with a maximal effect using 400 mU kg −1 insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy. Conclusion Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic.

Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer

Linomide, Figure 1, produces robust and consistent in vivo growth inhibition of prostate cancer models via its anti-angiogenic activity and inhibition of autoimmune encephalomyelitis models of multiple sclerosis (MS). MS clinical trials were discontinued because of unacceptable toxicity, due to dose-dependent induction of proinflammation. Therefore, linomide analogs were initially screened to determine their in vivo potency to inhibit growth of the Dunning R-3327 AT-1 rat prostate cancer model in rats and their potency to inhibit angiogenesis in a Matrigel assay in mice. Based upon its superior potency (i.e., 30- to 60-fold more potent than linomide) in these assays and its lack of a proinflammation in the Beagle-dog, ABR-215050 (tasquinimod), Figure 1, was characterized for dose-response ability to inhibit the growth of a series of four additional human and rodent prostate cancer models in mice. Pharmacokinetic analysis following oral dosing documented that blood and tumor tissue levels of ABR-215050 as low as 0.5-1 microM are therapeutically effective. This efficacy is correlated with inhibition of angiogenesis in a variety of assays (endothelial capillary tube formation, aortic ring assay, chorioallantoic membrane assay, real-time tumor blood flow and PO(2) measurements, tumor blood vessel density, and tumor hypoxic and apoptotic fractions). Based upon its robust and consistent anti-angiogenic activity and thus tumor growth, ABR-215050 has entered clinical trials for the treatment of prostate cancer.

Measurements of Partial Oxygen Pressure (pO2) using the OxyLite System in R3327-AT Tumors under Isoflurane Anesthesia

The presence of oxygen-deficient tumor cells is a critical issue in cancer therapy. To identify tumor hypoxia, tissue partial oxygen pressure (pO2) can be measured directly. The OxyLite system allows determination of pO2 in tumors and permits continuous measurements of pO2 at a fixed point. In this study, this system was used to continuously measure pO2 in R3327-AT tumors in animals anesthetized with isoflurane. In addition, continuous pO2 measurement was performed in the muscle in non-tumor-bearing animals. In animals breathing isoflurane balanced by air, tumor pO2 at fixed positions decreased rapidly within 1-2 min of probe positioning but remained stable thereafter. In animals breathing isoflurane balanced by pure oxygen, tumor pO2 was higher and remained high. We also measured pO2 values at multiple positions in R3327-AT tumors of various sizes, with anesthetized animals breathing either air or pure oxygen. Our data showed that the frequency of pO2 measurements below 2.5 or 5.0 mmHg was significantly higher in animals breathing air than in animals breathing pure oxygen. Measurements in different-sized tumors showed that the mean pO2 value decreased as tumor volume increased, with the largest change occurring between tumor volumes of 100 and 200 mm3. Our data demonstrate that the OxyLite system, when used with isoflurane anesthesia, is a valuable tool in the study of tumor hypoxia.

The prognostic value of pimonidazole and tumour pO 2 in human cervix carcinomas after radiation therapy: A prospective international multi-center study

Background and purpose Hypoxia adversely affects treatment outcome in human uterine cervical cancer. Here, we present the results of a prospective international multi-centre study evaluating the prognostic value of pre-treatment tumour oxygen partial pressure ( pO 2) and the hypoxia marker pimonidazole (pimo). Materials and methods One hundred and twenty-seven patients with primary cervix cancer were entered. Pre-treatment tumour pO 2 measurements were obtained, and reported by the median tumour pO 2, the fraction of pO 2 values ⩽10 mmHg (HP 10), ⩽5 mmHg (HP 5) and ⩽2.5 mmHg (HP 2.5). Following intravenous pimonidazole administration, biopsies were taken, stained for pimonidazole adducts, and scored for the area of labelled tumour cells on a scale from 0 to 4. Treatment modalities were surgery (11%), radiotherapy (98%), chemotherapy (33%) and carbogen (14%). Results None of the hypoxia descriptors were statistically significant prognostic factors for loco-regional tumour control or overall survival when analyzed as continuous variables or divided by the sample median. By univariate analysis only tumour size and nodal status were significant prognostic factors for local control. Tumour size and FIGO stage were significant for overall survival. In a multivariate analysis stratified by centre, only tumour size above 5 cm and lower pre-treatment haemoglobin predicted poorer overall survival among FIGO stage, nodal involvement, tumour size, pre-treatment haemoglobin dichotomized at 12 g/dl and pimo 1, pimo 4 and HP 5 as continuous variables. Conclusion Neither Eppendorf nor pimonidazole should be dismissed based on the current results. However, further investigations are needed to readdress the hypotheses of the current study having optimized statistical designs, and a population of sufficient size treated more homogenously following rigorous protocols.

Electron Paramagnetic Resonance Oxygen Images Correlate Spatially and Quantitatively with Oxylite Oxygen Measurements

Tumor oxygenation predicts cancer therapy response and malignant phenotype. This has spawned a number of oxymetries. Comparison of different oxymetries is crucial for the validation and understanding of these techniques. Electron paramagnetic resonance (EPR) imaging is a novel technique for providing quantitative high-resolution images of tumor and tissue oxygenation. This work compares sequences of tumor pO2 values from EPR oxygen images with sequences of oxygen measurements made along a track with an Oxylite oxygen probe. Four-dimensional (three spatial and one spectral) EPR oxygen images used spectroscopic imaging techniques to measure the width of a spectral line in each image voxel from a trityl spin probe (OX063, Amersham Health R&D) in the tissues and tumor of mice after spin probe injection. A simple calibration allows direct, quantitative translation of each line width to an oxygen concentration. These four-dimensional EPR images, obtained in 45 minutes from FSa fibrosarcomas grown in the legs of C3H mice, have a spatial resolution of approximately 1 mm and oxygen resolution of approximately 3 Torr. The position of the Oxylite track was measured within a 2-mm accuracy using a custom stereotactic positioning device. A total of nine images that involve 17 tracks were obtained. Of these, most showed good correlation between the Oxylite measured pO2 and a track located in the tumor within the uncertainties of the Oxylite localizability. The correlation was good both in terms of spatial distribution pattern and pO2 magnitude. The strong correlation of the two modalities corroborates EPR imaging as a useful tool for the study of tumor oxygenation.

WE‐D‐330A‐03: PO2 Measurements in Animal Tumors Using An Image‐Guided Robotic System

Purpose: To develop and evaluate an image‐guided robotic system for measuring pO2 in animal tumors. Method and Materials: The robot consists of an X‐Y horizontal platform holding the rodent bed, a dual‐axis vertical arm for positioning the measurement probe and cannula, and fiducial markers for registering the coordinates of the imaging and robotic systems. Anesthesized and immobilized tumor‐bearing rats are injected with the hypoxia tracer 18F‐FMISO and imaged in the rodent bed using an animal PET scanner. The reconstructed PET images are then uploaded into the robot computer, the rodent bed affixed to the X‐Y platform, and the coordinates of the robot and PET registered. Based on the tumor hypoxia image displayed on the robot computer, motion of the robotic X‐Y platform and vertical arm are coordinated to guide the positioning and percutaneous insertion of a probe (OxyLite‐Optronix) to measure pO2 at various locations in the tumor. The pO2 readings (cps/voxel) are then compared to the respective image intensity of the measurement points. Results: The registration accuracy between the robot and image coordinate system was better than 0.2mm. Although the 18F‐FMISO in the bladder produced characteristic starburst artifacts in the surrounding, low‐intensity regions, we successfully measured the pO2 for three tracks. The 18F‐FMISO image voxel values were found to be inversely correlated with the intra‐tumoral pO2 of the three tracks with (Pearson product moment) correlation coefficients of −0.899, −0.420 and −0.857. The scatter plot of pO2 vs. image intensity resembled a sigmoidal, rather than a linear relationship. Conclusion: PET‐guided pO2 measurement is feasible using this prototype image‐guided robot system. To our knowledge, this is the first system of its kind — allowing direct point‐by‐point correlation of physiological probe measurements and image voxel values or, more generally, a physical action at a set of anatomic points identified on a preoperative image.

An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non–Small Cell Lung Cancers

To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes. Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001). Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

104 The prognostic value of pimonidazole & tumor pO 2 in human cervix carcinomas after radiation therapy: An international multi-center study

104 The prognostic value of pimonidazole & tumor pO 2 in human cervix carcinomas after radiation therapy: An international multi-center study

Efaproxiral (RSR13) Plus Oxygen Breathing Increases the Therapeutic Ratio of Carboplatin in EMT6 Mouse Mammary Tumors

Carboplatin, a member of the platinum family of alkylating agents, is often used in combination with radiotherapy. Some studies, including a recent publication from our laboratory, have suggested that the cytotoxic effects of platinum compounds may be altered by changes in the post-treatment oxygenation. The study reported here assessed whether post-treatment changes in tumor oxygenation caused by oxygen breathing alone or in combination with efaproxiral (RSR13) altered the effects of carboplatin. Efaproxiral, which allosterically modifies hemoglobin-oxygen binding to increase tumor pO(2), has been shown to increase the effects of radiation in animal tumor models and is in a second, confirmatory phase III clinical trial as an adjuvant to radiotherapy. These studies with EMT6 tumors in BALB/c Rw mice used clonogenic assays to assess tumor cell survival and tumor growth studies to assess antineoplastic activity and treatment-related toxicity. Efaproxiral plus oxygen breathing for 5 hrs after carboplatin treatment significantly increased the antineoplastic effects of carboplatin. The increased antineoplastic effects of carboplatin produced by efaproxiral plus oxygen breathing occurred without a concomitant increase in host toxicity. These findings suggest that the increases in tumor oxygenation produced by Efaproxiral plus oxygen breathing increased the therapeutic ratio of carboplatin.

Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model

To examine dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a macromolecular contrast agent (P792) to visualize effects of radiotherapy (RT) on microvascular leakage in a colorectal cancer model. CC531 tumors were induced in WAG/Rij rats. DCE-MRI was performed before and 5 days after 5 x 5 Gy of RT and parametric maps generated of the endothelial transfer constant (K(trans)) and the fractional interstitial space (Ve) according to the Tofts model. Tissue pO2 mapping was performed in each tumor core and rim before and after RT. Microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and pimonidazole hypoxia staining were compared with a control group of tumor-bearing rats. Mean K(trans) and v(e) were significantly reduced after RT in all tumor regions. Mean pO2 was 6.8 mm Hg before RT vs. 7.7 mm Hg after RT (p < 0.001) in the tumor rim and 3.5 mm Hg before RT vs. 4.4 mm Hg after RT (p < 0.001) in the tumor core. Mean MVD in the tumor rim was 10.4 in the RT treated group vs. 16.9 in the control group (p = 0.061). VEGF expression was significantly higher in RT-treated rats. After RT, no correlation was found between DCE-MRI parameters and histologic parameters. A correlation was seen after RT between pO2 and K(trans) (r = -0.57, p = 0.08) and between pO2 and v(e) (r = -0.65, p = 0.04). Dynamic contrast-enhanced-MRI with P792 allows quantification of microvascular changes in this colorectal model. RT significantly reduces neovascular leakage and enhances tissue oxygenation and VEGF expression. After RT, DCE-MRI parameters are related to tumor pO2, but not to MVD or VEGF expression.

The role of vessel maturation and vessel functionality in spontaneous fluctuations ofT2*-weighted GRE signal within tumors

Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7 T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T2*w GRE sequence. This same sequence was also employed during air-5% CO2 breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling, alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation could explain at least in part the occurrence of spontaneous T2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction of fluctuations could still occur in non-perfused and/or immature vessels.

Anti-angiogenic therapy and chemotherapy affect 99mTc sestamibi and 99mTc-HL91 accumulation differently in tumour xenografts

Favourable effects of cytotoxic chemotherapy for tumours are characterized by the reduced accumulation of radiotracers such as 99mTc sestamibi (MIBI). Anti-angiogenic therapy is primarily cytostatic; consequently, its influence on tracer accumulation may differ from that of cytotoxic treatments. Anti-angiogenic therapy employing 2-methoxyestradiol was administered in mice bearing subcutaneous xenografts of LS180 colon cancer cells. The effects of chemotherapy with 5-fluorouracil were examined as a cytotoxic counterpart. Treatments were conducted for 4 days from day 8. Distribution of 99mTc-MIBI and Tc-HL91, a hypoxic marker, was observed on days 8 and 12. Oxygen tension (PO2) in tumours was measured by a microelectrode. Cellular uptake of tracers was examined in vitro in normoxic and hypoxic conditions. 99mTc-MIBI accumulation decreased with increasing tumour weight when no treatment was conducted. Tumour growth was suppressed by anti-angiogenic therapy and chemotherapy. 99mTc-MIBI accumulation in tumours decreased after chemotherapy as compared to pre-therapeutic values, whereas accumulation of 99mTc-HL91 increased. In contrast, accumulation of tracers did not significantly change after anti-angiogenic therapy as compared to that observed pre-therapeutically. Tumour PO2 decreased with increasing tumour volume when no treatment was conducted. Chemotherapy reduced PO2 in tumours. PO2 in tumours treated with anti-angiogenic therapy was as high as that observed before treatment. 2-Methoxyestradiol or 5-fluorouracil did not significantly affect tracer accumulation in cells under both normoxic and hypoxic conditions in vitro. These findings indicate that scintigraphic assessment of therapeutic efficacy of anti-angiogenic therapy should be performed from a perspective distinct from that of cytotoxic treatment.

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO2 (r=−0.091, P=0.59, n=87) or pimonidazole binding (r=0.13, P=0.45, n=38). There was no relationship between TP and HIF-1α, but there was a weak borderline significant relationship with HIF-2α expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P=0.032) and metastasis-free (P=0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.

A numerical coupling model to analyze the blood flow, temperature, and oxygen transport in human breast tumor under laser irradiation

The aim of this study is to investigate the variation of the blood perfusion rate and distribution of oxygen partial pressure ( PO 2 ) in human tumors by a coupling numerical model when laser irradiation is used as an adjuvant method in the treatment of cancer. A two-dimensional finite element (FE) thermal model of a human breast with a tumor was developed. The blood circulation inside the breast was modeled using one-dimensional non-linear equations of pulsatile fluid flow. The distribution of PO 2 inside the capillaries, tumor vessels, and surrounding tissue was obtained by the Krogh analysis model. Finally, the variations of the average tumor temperature, blood perfusion, and PO 2 during laser heating were computed by coupling the blood circulation, FE thermal, and oxygen transport models.

Observation of Increase of Oxygen in Experimental Murine Tumors Approximately 20 Minutes After X-Ray Irradiation

Purpose/Objective: The development of in vivo EPR oximetry now makes it feasible to follow the time course of oxygenation in tumors non-invasively, continuously, and repeatedly. In principle this should be very valuable because radiation response of hypoxic tumors is very sensitive to the level of oxygen and tumor growth, radiation therapy, and chemotherapy all potentially can change tumor pO2 dynamically. Using EPR continuously to follow early post-irradiation changes in RIF-1 tumors receiving fractionated radiation, we observed a previously unobserved transient increase in tumor oxygenation during the first hour.

Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study

Purpose To analyze the relationship between pre-treatment measurements of tumor oxygen tension (pO 2) and survival in advanced head and neck cancer. Patients and methods Eppendorf pO 2 measurements in 397 patients from seven centers were analyzed using the fraction of pO 2 values ≤2.5 mmHg (HP 2.5), ≤5 mmHg (HP 5) and median tumor pO 2 (mmHg) as descriptors. All patients had intended curative radiation therapy alone or as pre- or post-operative radiotherapy or radio-chemotherapy according to the practice at each center. Results The degree of hypoxia varied between tumors with an overall median tumor pO 2=9 mmHg (range 0–62 mmHg), a median HP 2.5=19% (range 0–97%) and HP 5=38%, (range 0–100%). By quadratic regression median tumor pO 2 correlated with Hb (2 P=0.026, n=357), while HP 2.5 or HP 5 did not. HP 2.5 above the population median was the only parameter that associated with poor overall survival (Kaplan Meier analysis, P=0.006). In a multivariate Cox Proportional Hazards analysis, stratified according to institution HP 2.5 was by far the most statistically significant factor in explaining the variability in survival. After adjusting for HP 2.5, clinical stage, radiation dose and surgery hemoglobin concentration was not significant in the model. The prognostic model shows that the 5-year survival is almost constant for HP 2.5 values in the range from 0 to 20%, whereas the 5-year survival approaches 0% in the most hypoxic tumors. Conclusion This study provides evidence that tumor hypoxia is associated with a poor prognosis in patients with advanced head and neck cancer.

Tumor physiologic response to combretastatin A4 phosphate assessed by MRI

To evaluate the effect of the vascular targeting agent, combretastatin A4 phosphate, on tumor oxygenation compared with vascular perfusion/permeability. (19)F MRI oximetry and dynamic contrast-enhanced (DCE)-MRI were used to monitor tumor oxygenation and perfusion/permeability in syngeneic 13762NF rat breast carcinoma. A significant drop was found in the mean tumor pO(2) (23 to 9 mm Hg, p <0.05) within 90 min after treatment (30 mg/kg of combretastatin A4 phosphate) and a further decrease was observed at 2 h (mean 2 mm Hg; p <0.01). The initial changes in pO(2) in the central and peripheral regions were parallel, but by 24 h after treatment, a significant difference was apparent: the pO(2) in the periphery had improved significantly, and the center remained hypoxic. These data are consistent with DCE-MRI, which revealed an approximately 70% decrease in perfusion/permeability (initial area under signal-intensity curve) at 2 h (p <0.001). The initial area under signal-intensity curve recovered fully after 24 h in a thin peripheral region, but not in the tumor center. The response observed by DCE-MRI, indicating vascular shutdown, paralleled the pO(2) measurements as expected, but quantitative pO(2) measurements are potentially important for optimizing the therapeutic combination of vascular targeting agents with radiotherapy.