Lung metastases treated by CyberKnife image-guided robotic stereotactic radiosurgery at 41 months.

OBJECTIVES: Based on the reported success of stereotactic body radiotherapy in treating extracranial tumors, we used CyberKnife (Accuray Incorporated, Sunnyvale, CA) to treat patients with metastatic lung cancer. METHODS: This is a retrospective report of treatment details and outcomes of 35 patients, ranging in age from 33 to 91 years, with 69 histologically proven pulmonary metastases, treated by image-guided robotic stereotactic radiosurgery at the CyberKnife Center of Miami, between March 2004 and August 2007. Tumor volumes ranged from 0.7 mL to 152 mL. Total doses ranged from 5 to 60 Gy delivered in one to four fractions with an equivalent dose range from 6 to 110 Gy NTD delivered in 2-Gy fractions assuming an alpha/beta of 20 Gy. RESULTS: All patients tolerated radiosurgery well with fatigue as the main side effect. Grade 3 and grade 4 pulmonary toxic reactions were observed in one patient who had undergone a repeat treatment. Of the 35 treated patients, 27 (77%) were still alive at a median 18-month (range 2-41 mo) follow-up. Local control was 71% with 25 tumors showing a complete response, 16 a partial response, and 7 stable with disease. Eight had progressive disease. CONCLUSIONS: The delivery of precisely targeted radiation doses to lung tumors in a hypofractionated fashion is feasible and safe. Image-guided robotic stereotactic radiosurgery of pulmonary metastases with the CyberKnife achieves good rates of local disease control with limited toxicity to surrounding tissues and in many cases may be beneficial for patients for whom surgery is not an option.

Early results of CyberKnife image-guided robotic stereotactic radiosurgery for treatment of lung tumors.

OBJECTIVE: To determine if image-guided robotic stereotactic radiosurgery (IGR-SRS) by CyberKnife achieves acceptable local control in resectable but medically inoperable patients with non-small cell lung cancer (NSCLC) or pulmonary metastasis, and to evaluate control rates and toxicity. METHODS: Treatment details and outcomes were reviewed for 95 patients (age range 33-96 years) with 136 histologically proven cancers treated by IGR-SRS at the CyberKnife Center of Miami between March 2004 and March 2007. Tumor volumes ranged from 1.2 cc to 338 cc. Targeting was accomplished using combined skeletal alignment and real-time tracking via fiducials placed within the tumor. Total doses ranged from 15 to 67.5 Gy delivered in 1 to 5 fractions. RESULTS: Of the 95 patients treated, 78 (82%) are still alive at 1 to 36 months post-treatment. Nineteen patients have died, four from disease other than cancer progression. All patients but one achieved at least partial response to treatment and tolerated radiosurgery well. For the majority of our patients, fatigue had been the main side effect. CONCLUSIONS: The delivery of precisely targeted high radiation doses with surgical precision to lung tumors in a hypo-fractionated fashion is feasible and safe. Image-guided robotic stereotactic radiosurgery (IGR-SRS) of lung tumors with the CyberKnife achieves excellent rates of local disease control with limited toxicity to surrounding tissues, and in many cases may be curative for patients for whom surgery is not an option.

CyberKnife radiosurgery for stage I lung cancer: results at 36 months.

PURPOSE: The aims of this study were to determine if image-guided robotic stereotactic radiosurgery by CyberKnife Radiosurgery System using ablative radiation doses achieves acceptable local control in medically inoperable patients with early non-small-cell lung cancer (NSCLC) and to evaluate disease-free survival, toxicity, and failure. CyberKnife can deliver the prescribed dose by using many different angles converging on the target, with real-time target tracking through a combined orthogonal radiograph imaging and optic motion tracking system (Synchrony). MATERIALS AND METHODS: A review of treatment details and outcomes for 59 patients, ranging in age from 51 years to 96 years, with 61 tumors with histologically proven cancers treated by image-guided robotic stereotactic radiosurgery at the CyberKnife Center of Miami between March 2004 and March 2007 is presented. Target localization and respiratory movement compensation were accomplished using a single fiducial marker placed within the tumor, and the X-Sight and Synchrony systems. Total doses ranged from 15 Gy to 67.5 Gy delivered in 1-5 fractions with an equivalent dose range of 24-110 Gy normalized treatment dose in 2 Gy fractions (alpha/beta = 20 Gy). RESULTS: Four patients with stage 1A NSCLC and 2 patients with stage 1B NSCLC had persistent or recurrent disease. All patients tolerated the radiosurgery well, fatigue being the main side effect. Of the 59 patients treated, 51 (86%) were still alive at 1-33-month follow-up. Eight patients have died, 2 of diseases other than cancer progression. CONCLUSION: The results indicate that the delivery of precisely targeted ablative radiation doses with surgical precision to limited treatment volumes of lung tumors in a hypofractionated fashion is feasible and safe. Image-guided robotic stereotactic radiosurgery of lung tumors with CyberKnife(R) achieves excellent rates of local disease control with limited toxicity to surrounding tissues and, in many cases, might be curative for patients for whom surgery is not an option.

Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei.

PURPOSE: We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme. EXPERIMENTAL DESIGN: In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article. We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy. We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme. RESULTS: With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.

Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR2) blockade.

The formation of new blood vessels (angiogenesis) represents a critical factor in the malignant growth of solid tumors and metastases. Vascular endothelial cell growth factor (VEGF) and its receptor VEGFR2 represent central molecular targets for antiangiogenic intervention, because of their integral involvement in endothelial cell proliferation and migration. In the current study, we investigated in vitro and in vivo effects of receptor blockade on various aspects of the angiogenic process using monoclonal antibodies against VEGFR2 (cp1C11, which is human specific, and DC101, which is mouse specific). Molecular blockade of VEGFR2 inhibited several critical steps involved in angiogenesis. VEGFR2 blockade in endothelial cells attenuated cellular proliferation, reduced cellular migration, and disrupted cellular differentiation and resultant formation of capillary-like networks. Further, VEGFR2 blockade significantly reduced the growth response of human squamous cell carcinoma xenografts in athymic mice. The growth-inhibitory effect of VEGFR2 blockade in tumor xenografts seems to reflect antiangiogenic influence as demonstrated by vascular growth inhibition in an in vivo angiogenesis assay incorporating tumor-bearing Matrigel plugs. Further, administration of VEGFR2-blocking antibodies in endothelial cell cultures, and in mouse xenograft models, increased their response to ionizing radiation, indicating an interactive cytotoxic effect of VEGFR2 blockade with radiation. These data suggest that molecular inhibition of VEGFR2 alone, and in combination with radiation, can enhance tumor response through molecular targeting of tumor vasculature.

Are gadolinium contrast agents suitable for gadolinium neutron capture therapy?

OBJECTIVE: Gadolinium neutron capture therapy (GdNCT) is a potential treatment for malignant tumors based on two steps: (1) injection of a tumor-specific (157)Gd compound; (2) tumor irradiation with thermal neutrons. The GdNC reaction can induce cell death provided that Gd is proximate to DNA. Here, we studied the nuclear uptake of Gd by glioblastoma (GBM) tumor cells after treatment with two Gd compounds commonly used for magnetic resonance imaging, to evaluate their potential as GdNCT agents. METHODS: Using synchrotron X-ray spectromicroscopy, we analyzed the Gd distribution at the subcellular level in: (1) human cultured GBM cells exposed to Gd-DTPA or Gd-DOTA for 0-72 hours; (2) intracerebrally implanted C6 glioma tumors in rats injected with one or two doses of Gd-DOTA, and (3) tumor samples from GBM patients injected with Gd-DTPA. RESULTS: In cell cultures, Gd-DTPA and Gd-DOTA were found in 84% and 56% of the cell nuclei, respectively. In rat tumors, Gd penetrated the nuclei of 47% and 85% of the tumor cells, after single and double injection of Gd-DOTA, respectively. In contrast, in human GBM tumors 6.1% of the cell nuclei contained Gd-DTPA. DISCUSSION: Efficacy of Gd-DTPA and Gd-DOTA as GdNCT agents is predicted to be low, due to the insufficient number of tumor cell nuclei incorporating Gd. Although multiple administration schedules in vivo might induce Gd penetration into more tumor cell nuclei, a search for new Gd compounds with higher nuclear affinity is warranted before planning GdNCT in animal models or clinical trials.

Factors affecting risk of symptomatic temporal lobe necrosis: significance of fractional dose and treatment time.

PURPOSE: To study the factors affecting the risk of symptomatic temporal lobe necrosis after different fractionation schedules. METHODS AND MATERIALS: One thousand thirty-two patients with T1-2 nasopharyngeal carcinoma treated with radical radiotherapy in Hong Kong during 1990-1995 were studied. They were treated at four different centers with similar techniques but different fractionation schedules: 984 patients were given 1 fraction daily throughout (q.d.), and 48 patients were irradiated twice daily (b.i.d.) for part of the course. The median total dose was 62.5 Gy (range 50.4-71.2), dose per fraction was 2.5 Gy (range 1.6-4.2), and overall treatment time (OTT) was 44 days (range 29-70). In addition, 500 patients received supplementary doses for parapharyngeal extension, 113 received booster doses by brachytherapy, and 114 received sequential chemotherapy using cisplatin-based regimes. RESULTS: Altogether, 24 patients developed symptomatic temporal lobe necrosis: 18 from the q.d. group and 6 from the b.i.d. group. The 5-year actuarial incidence ranged from 0% (after 66 Gy in 33 fractions within 44 days) to 14% (after 71.2 Gy in 40 fractions within 35 days). Multivariate analyses showed that the risk was significantly affected by the fractional effect of the product of total dose and dose per fraction (hazard ratio [HR] = 1.04, 95% confidence interval [CI] 1.02-1.05), OTT (HR 0.88, 95% CI 0.80-0.97), and b.i.d. scheduling (HR 13, 95% CI 3-54). Repeating the analyses for patients treated with the q.d. schedules confirmed the independent significance of OTT in addition to the product of total dose and dose per fraction. CONCLUSION: The tentative results suggest that in addition to fractional dose, the OTT also had significant impact on the risk of temporal lobe necrosis, and b.i.d. scheduling increased the hazard further.