Vivian P Cosgrove’s research while affiliated with Charité Universitätsmedizin Berlin and other places

Purpose: To assess hypofractionated stereotactic radiotherapy (H-SRT) with concurrent topotecan in patients with recurrent malignant glioma. Methods and Materials: Between February 1998 and December 2001, 25 patients with recurrent malignant glioma were treated in a phase I-H study (8 females and 17 males; median age, 45 years; range, 11-66 years; median Karnofsky performance status, 80%, range, 50-100%; median Mini Mental Standard Examination score, 25 points; range, 10-30 points). Of the 25 patients, 20% had World Health Organization Grade III and 80% World Health Organization Grade IV glioma. All patients had been treated previously by external beam radiotherapy with 54.4 Gy in 34 fractions twice daily, at least 6 h apart, within 3.5 weeks or 60 Gy in 30 fractions within 6 weeks. In addition, 84% had already received at least one chemotherapy regimen for recurrence. The median H-SRT dose at the 80% isodose was 25 Gy, and the maximal dose was 30 Gy delivered in five to six fractions on consecutive days. Topotecan (1.1 mg/m(2)/d) was given as a continuous i.v. infusion during H-SRT. Depending on the toxicity and compliance, patients received an additional 48 topotecan courses. Results: For all patients, the actuarial median progression-free survival was 10.5 months (range, 1.4-47.8 months), the median functional survival was 12.6 months (range, 1.6-49.5 months), and the median overall survival was 14.5 months (range, 3-56.4 months). Twelve percent of patients developed presumed adverse radiation effects (Radiation Therapy Oncology Group Grade 2). According to the Common Toxicity Criteria, version 2.0, no topotecan-related Grade 4 toxicity was noted. Grade 3 neutropenia was documented after 14 and Grade 3 thrombopenia. after 12 courses. Conclusion: H-SRT with topotecan is feasible and well-tolerated in patients with recurrent high-grade glioma and results in similar survival compared with other repeat treatment modalities. (c) 2006 Elsevier Inc.

Two systems have been developed for treating patients with locally advanced prostate cancer using intensity-modulated radiotherapy (IMRT): one using dynamic multi-leaf collimator delivery and the other using step-and-shoot. This paper describes the clinical implementation of these two techniques, and presents results from the first 14 patients treated in a clinical setting (nine dynamic, five step-and-shoot). Dynamic treatments were planned using Corvus, and step-and-shoot using Helax-TMS; all were delivered using Elekta accelerators. Prior to the first clinical treatments, validation measurements were carried out for each system, including measurements for a complete IMRT treatment. The reproducibility of dynamic delivery and the characteristics of the accelerator for low-monitor-unit (MU) deliveries were also assessed. An extensive quality assurance (QA) program was performed for each of the patients. Additionally, timing measurements were carried out to assess the practicalities of the technique. The planning objectives were met in most cases. Absolute doses for complete IMRT treatments were within 2%, on average, with dose distributions generally showing agreement within 3% or 3 mm. Beam modulation measurements made throughout each patient's treatment indicated that both delivery methods were reproducible. The dynamic plans required an average of 765 MU per beam, with a treatment delivery time of 14 min; corresponding results for step-and-shoot plans were 105 MU and 10 min. Two IMRT techniques for this group of patients have been successfully implemented in the clinic. The more complex dynamic treatments showed no advantages over the step-and-shoot approach. QA results have shown accurate and reproducible delivery for both techniques, giving increased confidence in the techniques and allowing a reduction in the QA program.

The development of intensity modulated radiotherapy (IMRT) has allowed the delivery of concave dose distributions. Planning studies have demonstrated the potential clinical benefit of IMRT in the treatment of the prostate and pelvic nodes in patients with advanced prostate cancer. As a consequence, IMRT was clinically implemented in the Royal Marsden NHS Trust in September 2000, using Elekta Sli series linear accelerators and NOMOS Corvus v3.0 planning system. As a relatively new treatment procedure in the United Kingdom, the clinical implementation involved developing appropriate quality assurance and verification procedures as well as training staff. This paper describes the practicalities of implementing IMRT into the routine workload of the radiotherapy department.

The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose-volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7-31.2% depending on the alpha/beta ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4-27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.

To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy. A treatment planning study was performed to compare two-phase conformal radiotherapy (CFRT) with IMRT in five patients. The CFRT plans consisted of anterior, posterior and bilateral posterior oblique fields, while the IMRT plans consisted of either nine equispaced fields (9F), or four fields (4F) with orientations equal to the CFRT plans. IMRT plans with seven, five or three equispaced fields were also investigated in one patient. Treatment plans were compared using dose-volume histograms and normal tissue complication probabilities. The 9F IMRT plan was unable to improve on the homogeneity of dose to the planning target volume (PTV), compared with the CFRT plan (dose range, 16.9+/-4.5 (1 SD) vs. 12.4+/-3.9%; P=0.06). Similarly, the 9F IMRT plan was unable to reduce the mean lung dose (11.7+/-3.2 vs. 11.0+/-2.9 Gy; P=0.2). Similar results were obtained for seven, five and three equispaced fields in the single patient studied. The 4F IMRT plan provided comparable PTV dose homogeneity with the CFRT plan (11.8+/-3.3 vs. 12.4+/-3.9%; P=0.6), with reduced mean lung dose (9.5+/-2.3 vs 11.0+/-2.9 Gy; P=0.001). IMRT using nine equispaced fields provided no improvement over CFRT. This was because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the CFRT fields offered an improvement in lung sparing. Thus, IMRT with a few carefully chosen field directions may lead to a modest reduction in pneumonitis, or allow tumour dose escalation within the currently accepted lung toxicity.

To assess 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques to see whether doses to critical structures could be reduced while maintaining planning target volume (PTV) coverage in patients receiving conventional radiotherapy (RT) for carcinoma of the maxillary sinus because of the risk of radiation-induced complications, particularly visual loss. Six patients who had recently received conventional RT for carcinoma of the maxillary sinus were studied. Conventional RT, 3D-CRT, and step-and-shoot IMRT plans were prepared using the same 2-field arrangement. The effect of reducing the number of segments in the IMRT beams was investigated. 3D-CRT and IMRT reduced the brain and ipsilateral parotid gland doses compared with the conventional plans. IMRT reduced doses to both optic nerves; for the contralateral optic nerve, 15-segment IMRT plans delivered an average maximal dose of 56.4 Gy (range 53.9-59.3) compared with 65.7 Gy (range 65.3-65.9) and 64.2 Gy (range 61.4-65.6) for conventional RT and 3D-CRT, respectively. IMRT also gave improved PTV homogeneity and improved coverage, with an average of 8.5% (range 7.0-11.7%) of the volume receiving <95% of the prescription dose (64 Gy) compared with 14.7% (range 14.1-15.9%) and 15.1% (range 14.4-16.1%) with conventional RT and 3D-CRT, respectively. Little difference was found between the 15 and 7-segment plans, but 5 segments resulted in a reduced minimal PTV dose. IMRT offers significant advantages over conventional RT and 3D-CRT techniques for treatment of maxillary sinus tumors. Good results can be obtained from 7 segments per beam without compromising the PTV coverage. This number of segments is practical for implementation in a busy RT department.

To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution. The planning target volume (PTV), contra-lateral parotid gland, oral cavity, brain-stem, brain and cochlea were outlined on CT planning scans of six patients with parotid gland tumours. Optimised conventional RT and 3DCRT plans were created and compared with inverse-planned IMRT dose distributions using dose-volume histograms. The aim was to reduce the radiation dose to organs at risk and improve the PTV dose distribution. A beam-direction optimisation algorithm was used to improve the dose distribution of the IMRT plans, and a class solution for parotid gland IMRT was investigated. 3DCRT plans produced an equivalent PTV irradiation and reduced the dose to the cochlea, oral cavity, brain, and other normal tissues compared with conventional RT. IMRT further reduced the radiation dose to the cochlea and oral cavity compared with 3DCRT. For nine- and seven-field IMRT techniques, there was an increase in low-dose radiation to non-target tissue and the contra-lateral parotid gland. IMRT plans produced using three to five optimised intensity-modulated beam directions maintained the advantages of the more complex IMRT plans, and reduced the contra-lateral parotid gland dose to acceptable levels. Three- and four-field non-coplanar beam arrangements increased the volume of brain irradiated, and increased PTV dose inhomogeneity. A four-field class solution consisting of paired ipsilateral coplanar anterior and posterior oblique beams (15, 45, 145 and 170 degrees from the anterior plane) was developed which maintained the benefits without the complexity of individual patient optimisation. For patients with parotid gland tumours, reduction in the radiation dose to critical normal tissues was demonstrated with 3DCRT compared with conventional RT. IMRT produced a further reduction in the dose to the cochlea and oral cavity. With nine and seven fields, the dose to the contra-lateral parotid gland was increased, but this was avoided by optimisation of the beam directions. The benefits of IMRT were maintained with three or four fields when the beam angles were optimised, but were also achieved using a four-field class solution. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.

External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated. A planning study was performed on patients with thyroid carcinoma. Plans were generated to irradiate the thyroid bed alone or to treat the thyroid bed and the loco-regional lymph nodes in two phases. Conventional plans with minimal beam shaping were compared to three-dimensional conformal radiotherapy (3DCRT) and inverse-planned IMRT plans to assess target coverage and normal tissue sparing. IMRT techniques were optimized to find the minimum number of equispaced beams required to achieve the clinical benefit and a concomitant boost technique was explored. For the thyroid bed alone and the thyroid bed plus loco-regional lymph nodes, conventional and conformal techniques produced low minimum doses to the planning target volume (PTV) if spinal cord tolerance was respected. 3DCRT reduced the irradiated volume of normal tissue (P=0.01). IMRT plans achieved the goal dose to the PTV (P<0.01) and also reduced the spinal cord maximum dose (P<0.01). IMRT, using a concomitant boost technique, produced better target coverage than a two-phase technique. For both the two-phase and concomitant boost techniques, IMRT plans with seven and five equispaced fields produced similar dose distributions to nine fields, but three fields were significantly worse. 3DCRT reduced normal tissue irradiation compared to conventional techniques, but did not improve PTV or spinal cord doses. IMRT improved the PTV coverage and reduced the spinal cord dose. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer.