Scanning irradiation device for mice in vivo with pulsed and continuous proton beams.

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 µm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.

Validation of the graded prognostic assessment index for patients with brain metastases.

BACKGROUND: The purpose of this study is to evaluate the performance of the new "Graded Prognostic Assessment" (GPA) index, which recently was developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients with brain metastases treated outside of randomized clinical trials. MATERIAL AND METHODS: The authors analyzed 232 patients with brain metastases and assigned these patients to the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases, and GPA). RESULTS: The present data confirm the results of the RTOG analysis. Each of the four indices splits the data set into prognostically different groups. In the GPA groups, median survival was 10.3, 5.6, 3.5, and 1.9 months, respectively (p<0.01). In the RTOG analysis, these figures were 11.0, 6.9, 3.8, and 2.6 months, respectively. CONCLUSION: These results confirm the validity of the GPA index in a patient population that most likely is more representative of the normal clinical situation than patients included in randomized trials.

Assessment of tumor volumes in skull base glomus tumors using Gluc-Lys[(18)F]-TOCA positron emission tomography.

PURPOSE: To assess a threshold for Gluc-Lys[(18)F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. METHODS AND MATERIALS: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[(18)F]-TOCA or with (68)Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. RESULTS: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. CONCLUSIONS: In patients with glomus tumors, Gluc-Lys[(18)F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[(18)F]-TOCA PET improves the accuracy of GTV delineation.

Validation of the graded prognostic assessment index for surgically treated patients with brain metastases.

The purpose of this study was to evaluate the performance of the new Graded Prognostic Assessment (GPA) index, which was recently developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients treated with surgical resection of brain metastases and postoperative whole-brain radiotherapy. The authors analyzed 64 patients and assigned each patient to each of the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases and GPA). The present data confirm the validity of the scoring systems in surgically treated patients. Each of the four indices splits the dataset into prognostically different groups; in the GPA groups, median survival was 18.9, 9.8, 5.5, and 3.7 months, respectively (p<0.05). In conclusion, these results confirm the validity of the GPA index in a patient population that previously has not been assessed with this new tool.

Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.

PURPOSE: Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment. METHODS: Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2-172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t (2vo). In addition to standard toxicity assessment, the major inner organs were examined histologically. RESULTS: The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t (2vo)) and led to a lethality rate of 15-30%. Higher TPZ doses caused an increase in t (2vo), but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity. CONCLUSIONS: This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.

The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas.

BACKGROUND: The objectives of this study were to investigate histomorphologic features as a response classification after neoadjuvant radiochemotherapy (RTx/CTx) and to correlate the results with clinical outcome parameters (e.g., postoperative morbidity and mortality, recurrence, and survival) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Three hundred eleven patients with histologically proven, locally advanced, intrathoracic ESCC (clinical T3 or T4, N0-N+, M0) located at or above the level of the tracheal bifurcation underwent preoperative, combined, simultaneous RTx/CTx followed by esophagectomy. Response to RTx/CTx was classified by the quantification of residual tumor cells. A histopathologic response was defined as <10% residual tumor cells found within the specimen compared with a histopathologic nonresponse, which was characterized by >10% residual tumor cells. RESULTS: A histopathologic response was correlated significantly with complete tumor resection status (R0 resection) (P .0001), histopathologic tumor (ypT) category (P <.0001), lymph node involvement (P <.0001), lymphatic vessel invasion (P <.001), and survival (P <.0001). A multivariate Cox regression analysis revealed that histopathologic response classification according to the percentage of residual tumor cells was an independent prognostic factor (P <.0001). Nonresponders had greater postoperative pulmonary morbidity (P = .01), a greater 30-day mortality rate (P = .02), and a dismal survival rate compared to histopathologic responders (P <.0001). CONCLUSIONS: Histopathologic response evaluation based on the quantification of residual tumor cells provided meaningful information for the assessment of outcomes among patients with ESCC who have underwent neoadjuvant RTx/CTx. The current results indicated that histopathologic responders may represent a subgroup of patients who benefit from neoadjuvant therapy followed by surgery.