High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years' experience with raster-scanned carbon ion therapy.

PURPOSE: Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck. PATIENTS AND METHODS: Treatment records of patients treated with C12 between 08/1998 and 05/2013 were evaluated regarding tumor stage, treatment, toxicity (CTCAE v3), LC, progression-free survival (PFS) and overall survival (OS). Response assessment was carried out according to RECIST1.1. RESULTS: Tumor stages were mostly advanced (T4a/b: 60%, macroscopic disease: 71%), most common sites of origin were the paranasal sinus (37%). At a median follow-up at 33.9 months, LC, PFS, and OS at 3 and 5 year estimates are 83.7%/58.5%, 67.8%/56.1%, and 88.9%/74.6%. LC correlates with T-stage but neither nodal stage, age, relapse state, nor margin status. RECIST did not correlate with LC or survival rates. CONCLUSION: IMRT plus C12 boost results in good control and survival rates at moderate toxicity. Margin status did not correlate with LC in T4 tumors, extensive and potentially mutilating surgical procedures may have to be re-evaluated. RECIST assessment did not correlate with either LC or survival rates; potentially more meaningful radiological parameters need to be developed.

Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival.

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.

First experiences with the implementation of the European standard EN 62304 on medical device software for the quality assurance of a radiotherapy unit.

BACKGROUND: According to the latest amendment of the Medical Device Directive standalone software qualifies as a medical device when intended by the manufacturer to be used for medical purposes. In this context, the EN 62304 standard is applicable which defines the life-cycle requirements for the development and maintenance of medical device software. A pilot project was launched to acquire skills in implementing this standard in a hospital-based environment (in-house manufacture). METHODS: The EN 62304 standard outlines minimum requirements for each stage of the software life-cycle, defines the activities and tasks to be performed and scales documentation and testing according to its criticality. The required processes were established for the pre-existent decision-support software FlashDumpComparator (FDC) used during the quality assurance of treatment-relevant beam parameters. As the EN 62304 standard implicates compliance with the EN ISO 14971 standard on the application of risk management to medical devices, a risk analysis was carried out to identify potential hazards and reduce the associated risks to acceptable levels. RESULTS: The EN 62304 standard is difficult to implement without proper tools, thus open-source software was selected and integrated into a dedicated development platform. The control measures yielded by the risk analysis were independently implemented and verified, and a script-based test automation was retrofitted to reduce the associated test effort. After all documents facilitating the traceability of the specified requirements to the corresponding tests and of the control measures to the proof of execution were generated, the FDC was released as an accessory to the HIT facility. CONCLUSIONS: The implementation of the EN 62304 standard was time-consuming, and a learning curve had to be overcome during the first iterations of the associated processes, but many process descriptions and all software tools can be re-utilized in follow-up projects. It has been demonstrated that a standards-compliant development of small and medium-sized medical software can be carried out by a small team with limited resources in a clinical setting. This is of particular relevance as the upcoming revision of the Medical Device Directive is expected to harmonize and tighten the current legal requirements for all European in-house manufacturers.

Accuracy of device-specific 2D and 3D image distortion correction algorithms for magnetic resonance imaging of the head provided by a manufacturer.

For the application of magnetic resonance imaging (MRI) in precision radiotherapy, image distortions must be reduced to a minimum to maintain geometrical accuracy. Recently, two-dimensional (2D) and three-dimensional (3D) algorithms for MRI-device-specific distortion corrections were developed by the manufacturers of MRI devices. A previously developed phantom (Karger C P et al 2003 Phys. Med. Biol. 48 211-21) was used to quantify and assess the size of geometrical image distortions before and after application of the 2D and 3D correction algorithm in the head region. Four different types of MRI devices with different gradient systems were measured. For comparison, measurements were also performed with two computed tomography (CT) devices. Mean distortions of up to 4.6+/-1.4 mm (maximum: 5.8 mm) were found prior to the correction. After the correction, the mean distortions were well below 2.0 mm in most cases. Distortions in the CT images were below or equal to 1.0 mm on average. Generally, the 3D algorithm produced comparable or better results than the 2D algorithm. The remaining distortions after the correction appear to be acceptable for fractionated radiotherapy.

Correction of patient positioning errors based on in-line cone beam CTs: clinical implementation and first experiences.

BACKGROUND: The purpose of the study was the clinical implementation of a kV cone beam CT (CBCT) for setup correction in radiotherapy. PATIENTS AND METHODS: For evaluation of the setup correction workflow, six tumor patients (lung cancer, sacral chordoma, head-and-neck and paraspinal tumor, and two prostate cancer patients) were selected. All patients were treated with fractionated stereotactic radiotherapy, five of them with intensity modulated radiotherapy (IMRT). For patient fixation, a scotch cast body frame or a vacuum pillow, each in combination with a scotch cast head mask, were used. The imaging equipment, consisting of an x-ray tube and a flat panel imager (FPI), was attached to a Siemens linear accelerator according to the in-line approach, i.e. with the imaging beam mounted opposite to the treatment beam sharing the same isocenter. For dose delivery, the treatment beam has to traverse the FPI which is mounted in the accessory tray below the multi-leaf collimator. For each patient, a predefined number of imaging projections over a range of at least 200 degrees were acquired. The fast reconstruction of the 3D-CBCT dataset was done with an implementation of the Feldkamp-David-Kress (FDK) algorithm. For the registration of the treatment planning CT with the acquired CBCT, an automatic mutual information matcher and manual matching was used. RESULTS AND DISCUSSION: Bony landmarks were easily detected and the table shifts for correction of setup deviations could be automatically calculated in all cases. The image quality was sufficient for a visual comparison of the desired target point with the isocenter visible on the CBCT. Soft tissue contrast was problematic for the prostate of an obese patient, but good in the lung tumor case. The detected maximum setup deviation was 3 mm for patients fixated with the body frame, and 6 mm for patients positioned in the vacuum pillow. Using an action level of 2 mm translational error, a target point correction was carried out in 4 cases. The additional workload of the described workflow compared to a normal treatment fraction led to an extra time of about 10-12 minutes, which can be further reduced by streamlining the different steps. CONCLUSION: The cone beam CT attached to a LINAC allows the acquisition of a CT scan of the patient in treatment position directly before treatment. Its image quality is sufficient for determining target point correction vectors. With the presented workflow, a target point correction within a clinically reasonable time frame is possible. This increases the treatment precision, and potentially the complex patient fixation techniques will become dispensable.

Evaluation of therapeutic potential of heavy ion therapy for patients with locally advanced prostate cancer.

PURPOSE: To investigate the feasibility of raster scanned heavy charged particle therapy in the treatment of prostate cancer (PCa,) with special regard to the influence of internal organ motion on the dose distribution. METHODS AND MATERIALS: The CT data of 8 patients with PCa who underwent three-dimensional conformal radiotherapy (RT) were chosen. In addition to the routine treatment planning scan, three to five additional positioning control CT scans were performed. The organs at risk and the target volumes were defined on all CT scans. Primary and boost carbon ion plans were calculated to deliver 66 Gy to the clinical target volume/planning target volume, with an additional 10 Gy to the gross tumor volume (GTV). To estimate the influence of internal organ motion on plan quality, the dose was recalculated on the basis of the control CT scans. The comparative analysis was based on the dose-volume histogram-derived physical parameters. RESULTS: The average 90% target coverage was 99.1% for the GTV. The maximal dose to the rectum was 71.8 Gy. The average rectal mean dose was 19 Gy. The volume of the rectum receiving 70 and 68 Gy was 0.1 and 0.3 cm3. The average difference in the 90% coverage for the GTV on control CT cubes was 3.6%. The maximal rectal dose increased to 76.2 Gy. The deviation in the mean rectal dose was <1 Gy on average. The rectal volume receiving 70 and 68 Gy increased to 2.5 and 3.3 cm3. CONCLUSION: The investigation demonstrated the feasibility of raster scanned carbon ions for PCa RT. Excellent coverage of the target volume and optimal sparing of the rectum were acquired. The combination of photon intensity-modulated RT and a carbon ion boost to the GTV is the most rational solution for the gain of clinical experience in heavy ion RT for PCa patients.

Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors.

PURPOSE: To characterize and quantitatively assess focal radiation reactions in the liver after stereotactic single-dose radiotherapy for liver malignancies. METHODS AND MATERIALS: A total of 131 multiphasic CT scans were performed in 36 patients before and after stereotactic radiotherapy for liver tumors. The examination protocol included a nonenhanced scan and contrast-enhanced scans at different times after contrast injection. The volume of the reaction was determined in each scan and the threshold dose calculated using the dose-volume histogram of the treatment plan. RESULTS: Every patient showed a focal radiation reaction on at least one follow-up examination. In 74% of the posttherapeutic scans, a sharply demarcated hypodense area surrounded the treated tumor in the nonenhanced scans. The reaction occurred at a median of 1.8 months (range 1.2-4.6) after radiotherapy. The median threshold dose was 13.7 Gy (range 8.9-19.2). The threshold dose strongly correlated with the time of detection after therapy (r = 0.7). Radiologically, three reaction types were found on the enhanced scans: type 1, portal-venous phase: hypodense and late phase: isodense; type 2, portal-venous phase: hypodense and late phase: hyperdense; and type 3, portal-venous phase: isodense/hyperdense and late phase: hyperdense. Type 1 or 2 reactions were observed significantly earlier than type 3 (p <0.05). The median threshold dose for type 1 or 2 reactions was significantly lower than for type 3 (p <0.05). The reaction volume decreased with longer follow-up (2-4 months: median 40% of initial volume). The reaction types shifted with follow-up: 58% were of type 1 at the initial manifestation and 58% were of type 3 at the next examination thereafter. CONCLUSION: A focal radiation reaction occurs after stereotactic single-dose therapy in the liver. The volume of the reaction decreases and changes its radiologic appearance during follow-up. This reaction has to be differentiated from recurrent tumor.

Stereotactic intensity-modulated radiation therapy (IMRT) and inverse treatment planning for advanced pleural mesothelioma. Feasibility and initial results.

BACKGROUND AND PURPOSE: Complex-shaped malignant pleural mesotheliomas (MPMs) with challenging volumes are extremely difficult to treat by conventional radiotherapy due to tolerance doses of the surrounding normal tissue. In a feasibility study, we evaluated if inversely planned stereotactic intensity-modulated radiation therapy (IMRT) could be applied in the treatment of MPM. PATIENTS AND METHODS: Eight patients with unresectable lesions were treated after failure of chemotherapy. All patients were positioned using noninvasive patient fixation techniques which can be attached to the applied extracranial stereotactic system. Due to craniocaudal extension of the tumor, it was necessary to develop a special software attached to the inverse planning program KonRad, which can connect two inverse treatment plans and consider the applied dose of the first treatment plan in the area of the matchline of the second treatment plan. RESULTS: Except for one patient, in whom radiotherapy was canceled due to abdominal metastasis, treatment could be completed in all patients and was well tolerated. Median survival after diagnosis was 20 months and after IMRT 6.5 months. Therefore, both the 1-year actuarial overall survival from the start of radiotherapy and the 2-year actuarial overall survival since diagnosis were 28%. IMRT did not result in clinically significant acute side effects. By using the described inverse planning software, over or underdosage in the region of the field matchline could be prevented. Pure treatment time ranged between 10 and 21 min. CONCLUSION: This study showed that IMRT is feasible in advanced unresectable MPM. The presented possibilities of stereotactic IMRT in the treatment of MPM will justify the evaluation of IMRT in early-stage pleural mesothelioma combined with chemotherapy in a study protocol, in order to improve the outcome of these patients. Furthermore, dose escalation should be possible by using IMRT.

Stereotactic imaging for radiotherapy: accuracy of CT, MRI, PET and SPECT.

CT, MRI, PET and SPECT provide complementary information for treatment planning in stereotactic radiotherapy. Stereotactic correlation of these images requires commissioning tests to confirm the localization accuracy of each modality. A phantom was developed to measure the accuracy of stereotactic localization for CT, MRI, PET and SPECT in the head and neck region. To this end. the stereotactically measured coordinates of structures within the phantom were compared with their mechanically defined coordinates. For MRI, PET and SPECT, measurements were performed using two different devices. For MRI, T1- and T2-weighted imaging sequences were applied. For each measurement, the mean radial deviation in space between the stereotactically measured and mechanically defined position of target points was determined. For CT, the mean radial deviation was 0.4 +/- 0.2 mm. For MRI, the mean deviations ranged between 0.7 +/- 0.2 mm and 1.4 +/- 0.5 mm, depending on the MRI device and the imaging sequence. For PET, mean deviations of 1.1 +/- 0.5 mm and 2.4 +/- 0.3 mm were obtained. The mean deviations for SPECT were 1.6 +/- 0.5 mm and 2.0 +/- 0.6 mm. The phantom is well suited to determine the accuracy of stereotactic localization with CT, MRI, PET and SPECT in the head and neck region. The obtained accuracy is well below the physical resolution for CT, PET and SPECT, and of comparable magnitude for MRI. Since the localization accuracy may be device dependent, results obtained at one device cannot be generalized to others.

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.