Secondary Malignancy Risk Following Proton vs. X-ray Radiotherapy of Thymic Epithelial Tumors: A Comparative Modeling Study of Thoracic Organ-Specific Cancer Risk.

BACKGROUND: Proton beam radiotherapy (PBT) offers physical dose advantages that might reduce the risk for secondary malignancies (SM). The aim of the current study is to calculate the risk for SM after X-ray-based 3D conformal (3DCRT) radiotherapy, intensity-modulated radiotherapy (IMRT), and active pencil beam scanned proton therapy (PBS) in patients treated for thymic malignancies. METHODS: Comparative treatment plans for each of the different treatment modalities were generated for 17 patients. The risk for radiation-induced SM was estimated using two distinct prediction models-the Dasu and the Schneider model. RESULTS: The total and fatal SM risks estimated using the Dasu model demonstrated significant reductions with the use of PBS relative to both 3DCRT and IMRT for all independent thoracic organs analyzed with the exception of the thyroid gland (p ≤ 0.001). SM rates per 10,000 patients per year per Gy evaluated using the Schneider model also resulted in significant reductions with the use of PBS relative to 3DCRT and IMRT for the lungs, breasts, and esophagus (p ≤ 0.001). CONCLUSIONS: PBS achieved superior sparing of relevant OARs compared to 3DCRT and IMRT, leading to a lower risk for radiation-induced SM. PBS should therefore be considered in patients diagnosed with thymic malignancies, particularly young female patients.

Secondary Malignancy Risk Following Proton vs. X-ray Treatment of Mediastinal Malignant Lymphoma: A Comparative Modeling Study of Thoracic Organ-Specific Cancer Risk.

Purpose: Proton radiotherapy (PRT) is potentially associated with a lower risk for secondary malignancies due to a decreased integral dose to the surrounding organs at risk (OARs). Prospective trials confirming this are lacking due to the need for long-term follow-up and the ethical complexities of randomizing patients between modalities. The objective of the current study is to calculate the risk for secondary malignancies following PRT and photon-based intensity-modulated radiotherapy (IMRT). Materials and Methods: Twenty-three patients (16 female and seven male), previously treated with active scanning PRT for malignant mediastinal lymphoma at Heidelberg Ion Beam Therapy Center, were retrospectively re-planned using helical photon IMRT. The risk for radiation-induced secondary malignancies was estimated and evaluated using two distinct prediction models (1-4). Results: According to the Dasu model, the median absolute total risk for tumor induction following IMRT was 4.4% (range, 3.3-5.8%), 9.9% (range, 2.0-27.6%), and 1.0% (range, 0.5-1.5%) for lung, breast, and esophageal cancer, respectively. For PRT, it was significantly lower for the aforementioned organs at 1.6% (range, 0.7-2.1%), 4.5% (range, 0.0-15.5), and 0.8% (range, 0.0-1.6%), respectively (p ≤ 0.01). The mortality risk from secondary malignancies was also significantly reduced for PRT relative to IMRT at 1.1 vs. 3.1% (p ≤ 0.001), 0.9 vs. 1.9% (p ≤ 0.001), and 0.7 vs. 1.0% (p ≤ 0.001) for lung, breast, and esophageal tumors, respectively. Using the Schneider model, a significant risk reduction of 54.4% (range, 32.2-84.0%), 56.4% (range, 16.0-99.4%), and 24.4% (range, 0.0-99.0%) was seen for secondary lung, breast, and esophageal malignancies, favoring PRT vs. X-ray-based IMRT (p ≤ 0.01). Conclusion: Based on the two prediction models, PRT for malignant mediastinal lymphoma is expected to reduce the risk for radiation-induced secondary malignancies compared with the X-ray-based IMRT. The young age and the long natural history of patients diagnosed with mediastinal lymphoma predisposes them to a high risk of secondary malignancies following curative radiotherapy treatment and, as a consequence, potentially reducing this risk by utilizing advanced radiation therapy techniques such as PRT should be considered.

Prospective feasibility analysis of a novel off-line approach for MR-guided radiotherapy.

BACKGROUND: The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies. PATIENTS AND METHODS: 20 patients with pelvic malignancies were included in this prospective feasibility analysis. Patients underwent daily MRI in treatment position prior to radiotherapy at the German Cancer Research Center. Positional inaccuracies, time and patient compliance were assessed for the application of off-line MRgRT. RESULTS: In 78% of applied radiation fractions, MR imaging for position verification could be performed without problems. Additionally, treatment-related side effects and reduced patient compliance were only responsible for omission of MRI in 9% of radiation fractions. The study workflow took a median time of 61 min (range 47-99 min); duration for radiotherapy alone was 13 min (range 7-26 min). Patient positioning, MR imaging and CT imaging including patient repositioning and the shuttle transfer required median times of 10 min (range 7-14 min), 26 min (range 15-60 min), 5 min (range 3-8 min) and 8 min (range 2-36 min), respectively. To assess feasibility of shuttle-based MRgRT, the reference point coordinates for the x, y and z axis were determined for the MR images and CT obtained prior to the first treatment fraction and correlated with the coordinates of the planning CT. In our dataset, the median positional difference between MR imaging and CT-based imaging based on fiducial matching between MR and CT imaging was equal to or less than 2 mm in all spatial directions. The limited space in the MR scanner influenced patient selection, as the bore of the scanner had to accommodate the immobilization device and the constructed stereotactic frame. Therefore, obese, extremely muscular or very tall patients could not be included in this trial in addition to patients for whom exposure to MRI was generally judged inappropriate. CONCLUSION: This trial demonstrated for the first time the feasibility and patient compliance of a shuttle-based off-line approach to MRgRT of pelvic malignancies.

4D-CT-based target volume definition in stereotactic radiotherapy of lung tumours: comparison with a conventional technique using individual margins.

PURPOSE: To investigate the dosimetric benefit of integration of 4D-CT in the planning target volume (PTV) definition process compared to conventional PTV definition using individual margins in stereotactic body radiotherapy (SBRT) of lung tumours. MATERIAL AND METHODS: Two different PTVs were defined: PTV(conv) consisting of the helical-CT-based clinical target volume (CTV) enlarged isotropically for each spatial direction by the individually measured amount of motion in the 4D-CT, and PTV(4D) encompassing the CTVs defined in the 4D-CT phases displaying the extremes of the tumour position. Tumour motion as well as volumetric and dosimetric differences and relations of both PTVs were evaluated. RESULTS: Volumetric examinations revealed a significant reduction of the mean PTV by 4D-CT from 57.7 to 40.7 cm(3) (31%) (p<0.001). A significant inverse correlation was found for the motion vector and the amount of inclusion of PTV(4D) in PTV(conv) (r=-0.69, 90% confidence limits: -0.87 and -0.34, p=0.007). Mean lung dose (MLD) was decreased significantly by 17% (p<0.001). CONCLUSIONS: In SBRT of lung tumours the mere use of individual margins for target volume definition cannot compensate for the additional effects that the implementation of 4D-CT phases can offer.

Radiobiological investigation of dose-rate effects in intensity-modulated radiation therapy.

BACKGROUND AND PURPOSE: Intensity-modulated radiation therapy (IMRT) has proven extraordinary capability in physical terms such as target conformity, dose escalation in the target volume, and sparing of neighboring organs at risk. The radiobiological consequences of the protracted dose delivery for cell survival and cell cycle progression are still unclear and shall be examined in this study. MATERIAL AND METHODS: Human lymphoblasts (TK6) and human melanoma cells (MeWo) were irradiated with protocols of increasing dose protraction. In addition, a new biophysical phantom was developed and used to transfer clinical IMRT plans to experimental cell irradiation. Clonogenic cell survival and cell cycle analysis were performed after various irradiation experiments. RESULTS: In a first series of experiments, melanoma cells showed a highly significant increase of survival of 6.0% after protracted dose delivery of 2 Gy compared to conventional fast application with the same dose. Lymphoblastoid cells also showed a significant increase of survival of 2.2%. Experiments with patient plans in the phantom confirmed the trend of increased cell survival after protracted dose delivery. Cells were irradiated at 13 points in four different IMRT plans. In comparison to irradiation with application of the same dose in a classic four-field box, a significantly increased survival of 5.1% (mean value) was determined. CONCLUSION: Even at fraction times of 15-30 min the protracted dose delivery increases the survival rates in cell culture. The altered survival rates indicate the importance of the dose rate in the effectivity of IMRT. Besides physical parameters the consideration of biological factors might contribute to the optimization of IMRT in the future.

Intensity modulated radiotherapy (IMRT) for recurrent, residual, or untreated skull-base meningiomas: preliminary clinical experience.

OBJECTIVE: To investigate the feasibility of using intensity modulated radiotherapy (IMRT) for complex-shaped benign meningiomas of the skull base and report clinical experience. METHODS: Twenty patients with benign skull-base meningiomas WHO degrees I (histopathologically proven in 16/20) were treated with IMRT between June 1998 and August 1999. Each tumor was complex in shape and adherent to, or encompassed, organs at risk (cranial nerves, optic apparatus, and brainstem). All patients, immobilized in a customized head mask integrated into a stereotactic system, were planned on an inverse treatment planning system using 5 or 7 coplanar, equidistant beams and 5 intensity steps. Each treatment plan was verified extensively before treatment. Follow-up with MRI and clinical examination was performed at 6 and 18 weeks and every 6 months thereafter. RESULTS: Target volumes ranged from 27 to 278 cc (median: 108 cc). Mean dose in 32 fractions ranged between 55.8 and 58.2 Gy. At median follow-up of 36 months (range: 31-43 months), pre-existing neurologic symptoms improved in 12/20 (60%), remained stable in 7/20 (35%), and worsened in 1 (5%) patient. Radiographic follow-up revealed significant tumor shrinkage 6 weeks post-IMRT in 2 patients and partial remission in 3 more patients at 9-17 months; other tumor volumes remained stable. There was no radiation-induced peritumoral edema, increase in tumor size, or new onset of neurologic deficits. Transient acute treatment side effects included nausea and vomiting and single occurrences of conjunctivitis/increased tearing and serous tympanitis. CONCLUSION: IMRT in the treatment of central nervous system meningiomas is feasible and safe, offering highly conformal irradiation for complex-shaped skull-base tumors while sparing adjacent critical structures. If the tumor remissions seen here are found in the ongoing treatments, IMRT may be considered the treatment of choice for inoperable or subtotally resected meningiomas and for otherwise difficult-to-treat, complex-shaped tumors of the central nervous system adjacent to critical structures, with the potential of dose escalation for malignant tumors.

Intensity-modulated radiotherapy of the female breast.

Current methods for intensity-modulated radiotherapy (IMRT) in breast cancer use forward planning based on equivalent radiological path length to design intensity modulated tangential beams. Compared to conventional tangential techniques, dose reduction of organs at risk is limited using these techniques. We developed a method for intensity modulation of multiple beams for adjuvant radiotherapy of breast cancer by application of a virtual bolus defined on CT for inverse optimization. This method enables multibeam IMRT, which provides improved sparing of lung and heart tissue. In this paper, we present the general aspects of this approach and an evaluation of the optimum beam configuration for IMRT based on inverse treatment planning. We compared this method to conventional techniques. Different clinical examples illustrate the possible indications and feasibility of this new approach. This method is superior to conventional techniques because of the reduction of high-dose area of a substantial cardiac volume in those cases where the parasternal lymph nodes are part of the target volume.