In vivo near-infrared spectroscopy and magnetic resonance imaging monitoring of tumor response to combretastatin A-4-phosphate correlated with therapeutic outcome.

PURPOSE: To develop a combination treatment consisting of combretastatin A-4-phosphate (CA4P) with radiation based on tumor oxygenation status. METHODS AND MATERIALS: In vivo near-infrared spectroscopy (NIRS) and diffusion-weighted (DW) magnetic resonance imaging (MRI) were applied to noninvasively monitor changes in tumor blood oxygenation and necrosis induced by CA4P (30 mg/kg) in rat mammary 13762NF adenocarcinoma, and the evidence was used to optimize combinations of CA4P and radiation treatment (a single dose of 5 Gy). RESULTS: NIRS showed decreasing concentrations of tumor vascular oxyhemoglobin and total hemoglobin during the first 2 h after CA4P treatment, indicating significant reductions in tumor blood oxygenation and perfusion levels (p < 0.001). Twenty-four hours later, in response to oxygen inhalation, significant recovery was observed in tumor vascular and tissue oxygenation according to NIRS and pimonidazole staining results, respectively (p < 0.05). DW MRI revealed significantly increased water diffusion in tumors measured by apparent diffusion coefficient at 24 h (p < 0.05), suggesting that CA4P-induced central necrosis. In concordance with the observed tumor oxygen dynamics, we found that treatment efficacy depended on the timing of the combined therapy. The most significant delay in tumor growth was seen in the group of tumors treated with radiation while the rats breathed oxygen 24 h after CA4P administration. CONCLUSIONS: Noninvasive evaluation of tumor oxygen dynamics allowed us to rationally enhance the response of syngeneic rat breast tumors to combined treatment of CA4P with radiation.

A dosimetric comparison of stereotactic body radiation therapy techniques for lung cancer: robotic versus conventional linac-based systems.

The aim of this study is to compare the dosimetric characteristics of robotic and conventional linac-based SBRT techniques for lung cancer, and to provide planning guidance for each modality. Eight patients who received linac-based SBRT were retrospectively included in this study. A dose of 60 Gy given in three fractions was prescribed to each target. The Synchrony Respiratory Tracking System and a 4D dose calculation methodology were used for CyberKnife and linac-based SBRT, respectively, to minimize respiratory impact on dose calculation. Identical image and contour sets were used for both modalities. While both modalities can provide satisfactory target dose coverage, the dose to GTV was more heterogeneous for CyberKnife than for linac planning/delivery in all cases. The dose to 1000 cc lung was well below institutional constraints for both modalities. In the high dose region, the lung dose depended on tumor size, and was similar between both modalities. In the low dose region, however, the quality of CyberKnife plans was dependent on tumor location. With anteriorly-located tumors, the CyberKnife may deliver less dose to normal lung than linac techniques. Conversely, for posteriorly-located tumors, CyberKnife delivery may result in higher doses to normal lung. In all cases studied, more monitor units were required for CyberKnife delivery for given prescription. Both conventional linacs and CyberKnife provide acceptable target dose coverage while sparing normal tissues. The results of this study provide a general guideline for patient and treatment modality selection based on dosimetric, tumor and normal tissue sparing considerations.

Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor.

PURPOSE: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. METHODS AND MATERIALS: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by (19)F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. RESULTS: Large tumors (>3.0 cm(3)) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO(2)) than their smaller counterparts (<1.5 cm(3)). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO(2), and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO(2) > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. CONCLUSIONS: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy.

Efficacy of high dose per fraction radiation for implanted human prostate cancer in a nude mouse model.

PURPOSE: SBRT is a new therapeutic paradigm using large dose per fraction treatments (aggressive hypofractionation). While SBRT has shown efficacy for treating patients with lung, liver and spine tumors, to our knowledge there have been no preclinical studies evaluating the efficacy of this treatment for prostate cancer. We investigated the dose-response characteristics of SBRT for treating human prostate cancer in a nude mouse model. MATERIALS AND METHODS: Nude mice were injected subcutaneously into the right flank with C4-2 prostate cancer cells grown in culture. A dose escalation trial was performed to assess toxicity and response. Tumor bearing animals were radiated with 3 fractions (1 per week) for a total dose of 15 Gy in 11, 22.5 Gy in 9 and 45 Gy in 10, while 8 untreated animals served as controls. The mice were weighed, and tumor volume and PSA measurements were performed at baseline and weekly until 4 weeks after treatment. RESULTS: There was no treatment related toxicity. There was a significant difference in the tumor response to higher radiation doses. In the 15 and 22.5 Gy groups mean tumor volume decreased to 58% and 90% of the original volume, respectively, but the rats experienced progressive tumor regrowth within 1 week after the completion of therapy. The 45 Gy group had a mean tumor volume and PSA decrease of greater than 90%, which was sustained 1 month after treatment in all except 2 mice. CONCLUSIONS: SBRT dose level treatments were able to significantly decrease tumor volume and PSA. However, using 15 and 22.5 Gy durable responses were not achieved except in a few mice. The 45 Gy group demonstrated sustained PSA and tumor volume decreases in most mice. These results clearly show an increasing dose-response relationship for a range of hypofractionated dose levels, as used in SBRT.

Efficacy of ablative high-dose-per-fraction radiation for implanted human renal cell cancer in a nude mouse model.

OBJECTIVES: Stereotactic body radiation therapy (SBRT) is a new therapeutic paradigm that uses a very large dose per fraction treatments (ablative hypofractionation). We investigated the use of ablative hypofractionation in treating human renal cell carcinoma using a nude mouse model. METHODS: Nude mice were injected subcutaneously with A498 human renal carcinoma cells. Tumour-bearing animals were radiated with three fractions (one per week) for a total dose of 48 Gy (n = 12), while untreated animals served as controls (n = 7). The mice were weighed, and tumour volumes were measured at baseline and weekly until 7 weeks post-treatment. RESULTS: Control animals demonstrated progressive tumour growth and were sacrificed because of either tumour size or ulceration. Tumours in the treatment group grew to three times their initial size over the 3 weeks of treatment but subsequently decreased progressively to less than 30% of their initial volume. All treated tumours exhibited marked cytologic changes. Tumours from mice sacrificed before post-treatment week 4 had a mitotic count of 1-4/10 hpf. Tumours from mice sacrificed more than 4 weeks post-treatment (n = 4) demonstrated no mitoses. CONCLUSIONS: Treatment with high-dose-per-fraction radiation to 48 Gy resulted in a sustained decrease in tumour volume and marked cytologic changes. These results are preliminary--but promising--and encourage further research into this application of ablative hypofractionated radiation for kidney cancer.

Correlation of tumor oxygen dynamics with radiation response of the dunning prostate R3327-HI tumor.

Our previous studies have shown that oxygen inhalation significantly reduces tumor hypoxia in the moderately well-differentiated HI subline of the Dunning prostate R3327 rat carcinoma. To test our hypothesis that modifying hypoxia could improve the radiosensitivity of these tumors, we performed experimental radiotherapy to compare the tumor response to ionizing radiation alone or in combination with oxygen inhalation. Tumor pO(2) measurements were performed on size-selected tumors several hours before radiotherapy using (19)F nuclear magnetic resonance echo planar imaging relaxometry (FREDOM) of the reporter molecule hexafluorobenzene. In common with our previous findings, the larger tumors (>3.5 cm(3)) exhibited greater hypoxia than the smaller tumors (<2 cm(3); P < 0.001), and oxygen inhalation reduced the hypoxic fraction (<10 Torr): In the larger tumors, hypoxic fraction dropped significantly from a mean baseline value of 80% to 17% (P < 0.001). The effect of oxygen administered 30 min before and during irradiation on tumor response to a single 30-Gy dose of photons was evaluated by growth delay. For the smaller tumors, no difference in growth delay was found when treatment was given with or without oxygen breathing. By contrast, breathing oxygen before and during irradiation significantly enhanced the growth delay in the larger tumors (additional 51 days). The differential behavior may be attributed to the low baseline hypoxic fraction (<10 Torr) in small tumors (20%) as a target for oxygen inhalation. There was a strong correlation between the estimated initial pO(2) value and the radiation-induced tumor growth delay (R > 0.8). Our histological studies showed a good match between the perfused vessels marked by Hoechst 33342 dye and the total vessels immunostained by anti-CD31 and indicated extensive perfusion in this tumor line. In summary, the present results suggest that the ability to detect modulation of tumor pO(2), in particular, the residual hypoxic fraction, with respect to an intervention, could have prognostic value for predicting the efficacy of radiotherapy.