Alan P. Warrington

Relocatable frame for stereotactic external beam radiotherapy

A non-invasive head fixation system is described which is accurately relocatable and enables the transfer of stereotactic positions between a variety of radiodiagnostic images and therapeutic procedures. The system can be simply and repeatedly applied for planning stereotactic radiation therapy from one or more diagnostic images and for repeated treatment with a conventional linear accelerator. In addition, the long-term effects of therapy can be objectively monitored by relocating the frame and repeating images in an identical way, months or years later.

PHASE III PILOT STUDY OF DOSE ESCALATION USING CONFORMAL RADIOTHERAPY IN PROSTATE CANCER: PSA CONTROL AND SIDE EFFECTS

Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3–6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58–81%) in the 74 Gy group vs 59% (95% CI 45–70%) in the 64 Gy group. There were 23 failures in the 74Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38–1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53–77% vs 63%, 95% CI 50–74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50–1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent ⩾Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG⩾2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade ⩾3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade⩾1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis.

Evaluation of the Delta4 phantom for IMRT and VMAT verification

The Delta(4) diode array phantom (Scandidos, Uppsala, Sweden) was evaluated for verification of segmental intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) on an Elekta linear accelerator (Crawley UK). The device was tested for angular sensitivity by irradiating it from 36 different gantry angles, and the responses of the device to various step-and-shoot segment doses and dose rates were evaluated using an ionization chamber as a comparison. The phantom was then compared with ionization chamber and film results for two prostate and pelvic nodes IMRT plans, two head and neck IMRT plans and two lung VMAT plans. These plans were calculated using Pinnacle(3) (Philips Radiation Oncology Systems, Madison, WI). The uniformity of angular response was better than 0.5% over the range of gantry angles. The uniformity of response of the Delta(4) to different segment monitor units and dose rates was better than 0.5%. The assessment of the IMRT and VMAT plans showed that the Delta(4) measured a dose within 2.5% of the ionization chamber, and compared to film recorded a slightly larger region (range -2% to +7%) agreeing with the planned dose to within 3% and 3 mm. The Delta(4) is a complex device and requires careful benchmarking, but following the successful completion of these measurements, the Delta(4) has been introduced into clinical use.

Hypofractionated stereotactic radiotherapy in the management of recurrent glioma

PURPOSE This study aimed to assess the efficacy and toxicity of hypofractionated stereotactic radiotherapy (SRT) in the management of patients with recurrent glioma. METHODS AND MATERIALS From January 1989 to July 1994, 36 patients with glioma were treated at the time of recurrence. Twenty-nine had recurrent high-grade astrocytoma, 3 high-grade oligodendroglioma, 1 high-grade ependymoma, and 3 pilocytic astrocytoma. Hypofractionated stereotactic radiotherapy was given using either three noncoplanar arcs or four to six noncoplanar fixed beams at 5 Gy/fraction, to doses ranging from 20 to 50 Gy initially on a dose escalation program. Two patients received 20 Gy, 8 received 30 Gy, 10 received 35 Gy, 10 received 40 Gy, 5 received 45 Gy, and 1 received 50 Gy, treating 5 days/week. RESULTS The median survival of 29 patients with recurrent high-grade astrocytoma was 11 months from the time of SRT. This compared to a median survival of 7 months for a cohort matched for age, performance status, and initial histologic grade who received nitrosourea-based chemotherapy at recurrence (p < 0.05). Initial low-grade astrocytoma histology was the only favorable prognostic factor for survival on univariate analysis. Three patients with recurrent oligodendroglioma remain alive 11, 23, and 34 months after SRT. Three children treated for recurrent pilocytic astrocytoma remain alive 14, 41, and 55 months following SRT. Presumed radiation damage, defined as reversible steroid-dependent toxicity, was observed in 13 patients (36%) and required reoperation in 2 (6%). A total dose of >40 Gy was a major predictor of radiation damage (p < 0.005). CONCLUSION Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose, focal irradiation.

Commissioning of Volumetric Modulated Arc Therapy (VMAT)

PURPOSE Volumetric modulated arc therapy (VMAT) involves the simultaneous use of dynamic multileaf collimator (DMLC) techniques and gantry arcing; appropriate quality assurance is therefore required. This article describes the development and implementation of procedures for commissioning VMAT on a commercial linear accelerator (Elekta PreciseBeam VMAT with MLCi and Beam Modulator heads). MATERIALS AND METHODS Tests for beam flatness and symmetry at the variable dose rates required for VMAT were performed. Multileaf collimator (MLC) calibration was investigated using dynamic prescriptions. The cumulative dose delivered by a sliding window aperture was measured and compared with calculated values. Rotational accuracy was evaluated using dynamic prescriptions which required accurate correlated motion of both gantry and MLC leaves. Finally, measured and calculated dose distributions for complete VMAT treatment plans were compared and evaluated. RESULTS Beam symmetry was found to be better than 3% down to dose rates of 75 MU/min. MLC calibration provided continuity of dose at match planes of better than 4%, which was comparable to interleaf leakage effects. Integrated sliding window doses were within 3% of those calculated. Tests for rotational accuracy showed uniformity of peripheral dose mostly within +/-4% of local control point dose, or approximately +/-0.2% of total central dose. A two-arc prostate case showed an absolute dose difference between calculations and measurements of less than 3%, with gamma (3% and 3 mm) of better than 95%. CONCLUSIONS VMAT has been successfully commissioned and has been introduced into clinical use. The Elekta DMLC has also been shown to be suitable for sliding window delivery.

RADIATION DOSE TO THE LENS AND CATARACT FORMATION

PURPOSE To determine the radiation tolerance of the lens of the eye and the incidence of radiation-induced lens changes in patients treated by fractionated supervoltage radiation therapy for orbital tumors. METHODS Forty patients treated for orbital lymphoma and pseudotumour with tumour doses of 20-40 Gy were studied. The lens was partly shielded using lead cylinders in most cases. The dose to the germinative zone of the lens was estimated by measurements in a tissue equivalent phantom using both film densitometry and thermoluminescent dosimetry. Ophthalmological examination was performed at 6 monthly intervals after treatment. RESULTS The lead shield was found to reduce the dose to the germinative zone of the lens to between 36-50% of the tumor dose for Cobalt beam therapy, and to between 11-18% for 5 MeV x-rays. Consequently, the len doses were in the range 4.5-30 Gy in 10-20 fractions. Lens opacities first appeared from between 3 and 9 years after irradiation. Impairment of visual acuity ensued in 74% of the patients who developed lens opacities. The incidence of lens changes was strongly dose-related. None was seen after doses of 5 Gy or lower, whereas doses of 16.5 Gy or higher were all followed by lens opacities which impaired visual acuity. The largest number of patients received a maximum lens dose of 15 Gy; in this group the actuarial incidence of lens opacities at 8 years was 57% with visual impairment in 38%. CONCLUSION The adult lens can tolerate a total dose of 5 Gy during a fractionated course of supervoltage radiation therapy without showing any changes. Doses of 16.5 Gy or higher will almost invariably lead to visual impairment. The dose which causes a 50% probability of visual impairment is approximately 15 Gy.

A comparison of clinical target volumes determined by CT and MRI for the radiotherapy planning of base of skull meningiomas

PURPOSE To assess the utility of image registration and to compare the localization of clinical target volumes (CTV) using CT and MRI for patients with base of skull meningiomas undergoing radiotherapy. METHODS AND MATERIALS Seven patients were imaged using CT and a T1-weighted MR volumetric sequence. Following image registration using a chamfer-matching algorithm, transaxial MR slices were reconstructed to match the planning CT slices. The accuracy of the image fusion was assessed in a preliminary study with matching accuracy better than 1.5 mm. The CTV in each patient was separately segmented by two independent observers for both CT and reconstructed MR image sets. Scalar and vector assessments were made of the difference in radial extent between the two outlines on each transaxial plane for all patients. A positive vector value corresponded to a greater extension of the tumor on MR compared to CT and vice versa. Scalar measurements compared the modulus of the differences between MR and CT, regardless of which volume was more extensive. Qualitative comparisons were also performed. RESULTS Interobserver difference was small with a mean (+/- 1SD) volume difference of 1.5 +/- 1.5 cm(3) for CT and 0.5 +/- 1.0 cm(3) for MRI. The mean CT- and MR- CTVs were 17.6 +/-10.8 and 19.6 +/-14.2 cm(3) respectively. The mean overlap and composite volumes were 13.8 +/-10. 1 and 23.3 +/-14.8 cm(3) respectively. Average scalar differences in the left, right, anterior, and posterior directions were 6.0 +/- 7.0, 3.3 +/- 2.5, 4.9 +/- 3.9, and 4.5 +/- 5.0 mm respectively. The average vector differences were 3.3 +/- 8.5, -0.3 +/- 3.8, 1.1 +/- 5. 8, 1.5 +/- 6.4 mm (for left, right, anterior, and posterior directions respectively). Qualitatively, MR appeared to discern more tumor involvement in soft tissue regions adjacent to the skull base whereas CT appeared to provide larger target volumes within bony regions. CONCLUSIONS MRI appeared to define CTVs that were larger but not inclusive of CT-defined CTVs. Although the average vector differences were small, the differences on individual borders could be large. In some instances, the CT or MR volumes were vastly different, each providing separate information. Therefore, the use of MRI and CT is complementary. Until accurate histological confirmation of disease extent is available, it is prudent to consider composite CT/MR volumes for the radiotherapy planning of base of skull meningiomas.

A non-invasive, relocatable stereotactic frame for fractionated radiotherapy and multiple imaging

A non-invasive relocatable stereotactic frame has been developed for fractionated stereotactic external beam radiotherapy (SRT) by linear accelerator. Fixation is via the upper dentition and tests of repositioning have shown mean antero-posterior and lateral displacements of 1.0 mm. The relocatable frame allows accurate 3-dimensional target localisation by CT, MRI, PET and cerebral angiography and precise isocentric positioning for radiotherapy. This method of immobilisation is ideal for fractionated SRT as well as for other techniques requiring high precision localisation and treatment delivery.

Efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent gliomas (phase I/II study)*

Twenty-two patients with recurrent glioma have been treated on a dose escalation protocol with fractionated stereotactic external beam radiotherapy (SRT). All had previously received radical radiotherapy (median dose 55 Gy) as part of the initial treatment. The dose of SRT was increased from 30 Gy in six fractions to 50 Gy in ten fractions. Median survival from the date of SRT was 9.8 months. There was no significant acute morbidity but five patients who received > or = 40 Gy developed steroid responsive neurological deterioration assumed to represent late radiation damage. The survival and toxicity in patients with recurrent glioma are comparable with interstitial therapy. Fractionated SRT is a noninvasive form of localised radiation which may be a suitable alternative to interstitial therapy in this group of patients.

Stereotactically guided conformal radiotherapy for progressive low-grade gliomas of childhood.

PURPOSE To describe the rationale, technique, and early results of stereotactically guided conformal radiotherapy (SCRT) in the treatment of progressive or inoperable low-grade gliomas (LGGs) of childhood. METHODS AND MATERIALS Between September 1994 and May 1999, 14 children (median age 6 years, range 5-16) with LGG were treated with SCRT at the Royal Marsden NHS Trust. Tumors were located at the optic chiasm (n = 9), third ventricle (n = 2), hypothalamus, craniocervical junction, and pineal region (each n = 1). Four patients received chemotherapy before SCRT. Immobilization was in a Gill-Thomas-Cosman frame (n = 12) and subsequently in a specially designed pediatric version of the frame (n = 2). Stereotactic coordinates and the tumor were defined by CT scanning with a fiducial system and MRI fusion. The median tumor volume was 19.5 cm(3) (range 7.5-180). The planning target volume was defined as the area of enhancing tumor plus a 5-10-mm margin. The treatment technique consisted of 4 isocentric, noncoplanar, conformal, fixed fields. Treatment was delivered in 30-33 daily fractions to a total dose of 50-55 Gy. RESULTS SCRT was well tolerated, with transient hair loss the only acute toxicity. The median follow-up was 33 months (range 2-53). At 6 months after SCRT, 4 of 12 children with neurologic deficits improved and 5 remained stable. Twelve children were available for MRI evaluation. Two had a complete response, 6 a partial response, and 4 stable disease. One child with optic chiasm glioma had local progression at 25 months, and 1 developed diffuse leptomeningeal disease without local progression at 27 months. The 3-year local progression-free survival and overall survival rate after SCRT was 87% and 100%, respectively, compared with 89% and 98% for an historic control treated with conventional RT. New endocrine deficiencies were noted in 2 children after a follow-up of 20 and 23 months. CONCLUSION SCRT is a feasible, high-precision technique of RT for children with LGGs for whom RT is considered appropriate. The local control and acute toxicity of SCRT are comparable to a historic control of patients with conventionally delivered RT. The frequency of delayed hypothalamic-pituitary axis dysfunction reflects tumor location adjacent to the hypothalamus and pituitary. Additional follow-up is required to demonstrate that SCRT contributes to a reduction in treatment-related late toxicity, while maintaining the local control achieved with conventionally delivered RT in children with progressive LGGs.