Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer.

AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

A multicentre audit of HDR/PDR brachytherapy absolute dosimetry in association with the INTERLACE trial (NCT015662405).

A UK multicentre audit to evaluate HDR and PDR brachytherapy has been performed using alanine absolute dosimetry. This is the first national UK audit performing an absolute dose measurement at a clinically relevant distance (20 mm) from the source. It was performed in both INTERLACE (a phase III multicentre trial in cervical cancer) and non-INTERLACE brachytherapy centres treating gynaecological tumours. Forty-seven UK centres (including the National Physical Laboratory) were visited. A simulated line source was generated within each centre's treatment planning system and dwell times calculated to deliver 10 Gy at 20 mm from the midpoint of the central dwell (representative of Point A of the Manchester system). The line source was delivered in a water-equivalent plastic phantom (Barts Solid Water) encased in blocks of PMMA (polymethyl methacrylate) and charge measured with an ion chamber at 3 positions (120° apart, 20 mm from the source). Absorbed dose was then measured with alanine at the same positions and averaged to reduce source positional uncertainties. Charge was also measured at 50 mm from the source (representative of Point B of the Manchester system). Source types included 46 HDR and PDR 192Ir sources, (7 Flexisource, 24 mHDR-v2, 12 GammaMed HDR Plus, 2 GammaMed PDR Plus, 1 VS2000) and 1 HDR 60Co source, (Co0.A86). Alanine measurements when compared to the centres' calculated dose showed a mean difference (±SD) of +1.1% (±1.4%) at 20 mm. Differences were also observed between source types and dose calculation algorithm. Ion chamber measurements demonstrated significant discrepancies between the three holes mainly due to positional variation of the source within the catheter (0.4%-4.9% maximum difference between two holes). This comprehensive audit of absolute dose to water from a simulated line source showed all centres could deliver the prescribed dose to within 5% maximum difference between measurement and calculation.

Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up.

BACKGROUND: Radical three-dimensional conformal radiotherapy (CFRT) with initial androgen suppression (AS) is a standard management for localised prostate cancer (PC). This pilot study evaluated the role of dose escalation and appropriate target volume margin. Here, we report long-term follow-up. METHODS: Eligible patients had T1b-T3b N0 M0 PC. After neoadjuvant AS, they were randomised to CFRT, giving (a) 64 Gy with either a 1.0- or 1.5-cm margin and (b) ±10 Gy boost to the prostate alone. RESULTS: One hundred and twenty-six men were randomised and treated. Median follow-up was 13.7 years. The median age was 66.6 years at randomisation. Median presenting prostate-specific antigen (PSA) was 14 ng ml(-1). Sixty-four out of 126 patients developed PSA failure. Forty-nine out of 126 patients restarted AS, 34 out of 126 developed metastases and 28 out of 126 developed castrate-resistant prostate cancer (CRPC). Fifty-one out of 126 patients died; 19 out of 51 died of PC. Median overall survival (OS) was 14.4 years. Although escalated dose results were favourable, no statistically significant differences were seen between the randomised groups; PSA control (hazard ratio (HR): 0.77 (95% confidence interval (CI): 0.47-1.26)), development of CRPC (HR: 0.81 (95% CI: 0.40-1.65)), PC-specific survival (HR: 0.59 (95% CI:0.23-1.49)) and OS (HR: 0.81 (95% CI: 0.47-1.40)). There was no evidence of a difference in PSA control according to margin size (HR: 1.01 (95% CI: 0.61-1.66)). INTERPRETATION: Long-term follow-up of this small pilot study is compatible with a benefit from dose escalation, but confirmation from larger trials is required. There was no obvious detriment using the smaller radiotherapy margin.

Electron dosimetry of angular fields.

Shaping electron fields through the use of lead cut-outs may result in there being acute angles in part of the field. Using both experimental techniques and EGSnrc Monte Carlo simulations an investigation was carried out to determine the dosimetric consequences of this. Measurements were made to investigate how the field dose was related to the angle between adjacent sides in the cut-outs. The study involved two electron energies (9 MeV and 12 MeV) and source-skin distances (SSDs) in the range 1000-1100 mm. For angles less than about 120 degrees the dose received in the angular region decreased significantly, the effect being more pronounced at 12 MeV than at 9 MeV, and at longer SSDs. The planar shapes of the Monte Carlo dose distributions agreed with those experimentally determined to within +/-1.5 mm at 9 MeV and +/-1.0 mm at 12 MeV, demonstrating the validity of using such calculations for this purpose. Graphs are presented which may help in the prospective assessment of the dose reductions likely to be incurred.

Movement of the cervix in after-loading brachytherapy: implications for designing external-beam radiotherapy boost fields.

AIMS: Women with invasive carcinoma of the cervix treated by chemo-radiotherapy and brachytherapy may also receive a pelvic sidewall boost using a midline shield (MLS). The purpose of this study was to assess the usefulness of implanted gold grains in detecting the movement of the cervix caused by the insertion of low-dose-rate brachytherapy applicators, and its implications in designing the MLS. MATERIALS AND METHODS: The medical records of 42 women with various stages of cervical carcinoma, who were treated by radical chemo-radiotherapy, were reviewed. All of these women underwent examination under anaesthesia (EUA) and a gold-grain insertion to demarcate the vaginal tumour extent, in the antero-posterior and lateral planes, before starting external-beam radiotherapy. The isocentric orthogonal films (simulator films) of external radiotherapy and brachytherapy were compared to assess the change in position of the gold grains and the consequences for the design of the MLS for parametrial and pelvic sidewall boosts. RESULTS: A significant shift in the position of the gold grains was noted in both the x (lateral) and the y (cranial/caudal) axes. The median shift of the midline, right and left lateral gold grains was 4.5, 5 and 7 mm in the x axis, whereas it was 10, 8 and 9.5 mm in the y axis, respectively. The median shift in the x and y axes was 5.5 and 9 mm, ranging from 1 to 40 mm and 1 to 45 mm, respectively. The gold grains were shifted cranially in 34 (80%) and laterally in 29 (69%) women. Thirty-two women (76.2%) received parametrial boost radiotherapy, of which 25 (59.5%) women had a customised, pear-shaped shield, and the remaining seven (16.7%) had a straight-sided, rectangular MLS. Four women (9.5%) relapsed locally, and three of them had been treated using a customised shield. In two of these four women, there was an absolute under-dosage of the central pelvis at the tip of the intra-uterine tube by 50% of the parametrial boost dose (5.4 Gy/3 fractions/3 days). CONCLUSIONS: Insertion of the gold grains during pre-treatment EUA is a useful technique in detecting the movement of the cervix. A significant shift in the position of the gold grains was noted in both the x (lateral) and the y (cranial/caudal) axes. These shifts in the cervix can result in under-dosage of the central pelvis when delivering parametrial boosts with the MLS in place on the basis of the brachytherapy check films. When designing the individualised MLS, the resulting under-dosage could be avoided by taking account of the shift in the gold grain markers and allow the delivery of a more homogenous dose to the pelvis.

Head-and-neck IMRT treatments assessed with a Monte Carlo dose calculation engine.

IMRT is frequently used in the head-and-neck region, which contains materials of widely differing densities (soft tissue, bone, air-cavities). Conventional methods of dose computation for these complex, inhomogeneous IMRT cases involve significant approximations. In the present work, a methodology for the development, commissioning and implementation of a Monte Carlo (MC) dose calculation engine for intensity modulated radiotherapy (MC-IMRT) is proposed which can be used by radiotherapy centres interested in developing MC-IMRT capabilities for research or clinical evaluations. The method proposes three levels for developing, commissioning and maintaining a MC-IMRT dose calculation engine: (a) development of a MC model of the linear accelerator, (b) validation of MC model for IMRT and (c) periodic quality assurance (QA) of the MC-IMRT system. The first step, level (a), in developing an MC-IMRT system is to build a model of the linac that correctly predicts standard open field measurements for percentage depth-dose and off-axis ratios. Validation of MC-IMRT, level (b), can be performed in a rando phantom and in a homogeneous water equivalent phantom. Ultimately, periodic quality assurance of the MC-IMRT system is needed to verify the MC-IMRT dose calculation system, level (c). Once the MC-IMRT dose calculation system is commissioned it can be applied to more complex clinical IMRT treatments. The MC-IMRT system implemented at the Royal Marsden Hospital was used for IMRT calculations for a patient undergoing treatment for primary disease with nodal involvement in the head-and-neck region (primary treated to 65 Gy and nodes to 54 Gy), while sparing the spinal cord, brain stem and parotid glands. Preliminary MC results predict a decrease of approximately 1-2 Gy in the median dose of both the primary tumour and nodal volumes (compared with both pencil beam and collapsed cone). This is possibly due to the large air-cavity (the larynx of the patient) situated in the centre of the primary PTV and the approximations present in the dose calculation.

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 74 Gy 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 > or =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> or =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 > or =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> or =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.

Target volume definition in conformal radiotherapy for prostate cancer: quality assurance in the MRC RT-01 trial.

BACKGROUND AND PURPOSE: Prior to randomization of patients into the UK Medical Research Council multicentre randomized trial (RT-01) of conformal radiotherapy (CFRT) in prostate cancer, clinicians at participating centres were required to complete a quality assurance (QA) clinical planning exercise to enable an investigation of inter-observer variability in gross target volume (GTV) and normal structure outlining. MATERIALS AND METHODS: Thirteen participating centres and two investigators completed the clinical planning exercise of three practice planning cases. Clinicians were asked to draw outlines of the GTV, rectum and bladder on hard-copy computerized tomography (CT) films of the pelvis, which were transferred onto the Cadplan computer planning system by a single investigator. Centre, inferior and superior CT levels of GTV, rectum and bladder were noted, and volume calculations performed. Planning target volumes (PTV) were generated using automatic volume expansion of GTVs by a 1 cm margin. Anterior, right and left lateral beam eye views (BEV) of the PTVs were generated. Using a common central point, the BEV PTVs were superimposed for each beam direction of each case. Radial PTV variation was investigated by measurement of a novel parameter, termed the radial line measurement variation (RLMV). RESULTS: GTV central slice and length were defined with reasonable consistency. The RLMV analysis showed that the main part of the prostate gland, bladder and inferior rectum were outlined with good consistency among clinicians. However, the outlining of the prostatic apex, superior aspect of the prostate projecting into the bladder, seminal vesicles, the base of seminal vesicles and superior rectum were more variable. CONCLUSION: This exercise has demonstrated adequate consistency of GTV definition. The RLMV method of analysis indicates particular regions of clinician uncertainty. Appropriate feedback has been given to all participating clinicians, and the final RT-01 trial protocol has been modified to accommodate these findings.

Radiotherapy planning techniques for thyroid cancer.

External beam radiotherapy has a role in each histological type of thyroid cancer. For treatment confined to the thyroid bed, an antero--oblique wedged pair of beams is simple to apply. More frequently, however, the volume needs to include both sides of the neck and adequate dose must be given down to the level of the suprasternal notch, precluding use of lateral fields. Thus, anterior and posterior fields are usually necessary, extending from the tips of the mastoid processes or hyoid down to the carina and laterally to include both sides of the neck and supraclavicular fossae. The mandible and infraclavicular portions of both lungs are shielded, but there is no midline lead in the phase one volume. A mid-plane dose of 46 Gy given in 23 daily fractions results in an acceptable early radiation reaction and will avoid late damage to the spinal cord. Because of considerable variation of interplanar distance along the length of the volume, a lateral simulator film should be taken to determine the maximum cord dose. For most patients, a three-dimensional CT planned phase two volume will be required and should be determined prior to completing phase one. The optimum beam arrangement, usually incorporating conformal beam shaping assisted by use of a multileaf collimator, should avoid further dose to the cord. If there is additional dose to the spinal cord, this phase can be introduced before 46 Gy is reached.

Pictorial review: comparison of portal imaging and megavoltage verification films for conformal pelvic irradiation.

This study has evaluated the use of electronic portal imaging (EPI) as a replacement for megavoltage verification films in the treatment of conformal pelvic patients. The two methods of imaging have been compared in 40 patients. Several advantages of EPI were identified, including case of image acquisition. regular assessment of reproducibility of set-up and the possibility of on-line intervention when necessary. The findings suggest that EPI is a suitable replacement for films.

Radiotherapy of brain tumours: reduced irradiation of normal brain.

We analysed the dose-volume distribution in normal brain in eight patients undergoing localized external beam radiotherapy for brain tumours. The results have been represented as integral dose-volume histograms and show that large volumes of normal brain receive clinically significant doses of radiation. A mean of 43% (range 24%-57%) of normal brain volume received more than 50% and a mean of 22% (range 9%-38%) received more than 85% of the maximum tumour dose. The amount of normal brain irradiated increased with enlarging target volume. With the use of customized shielding blocks the mean volume reduction of normal brain receiving more than 50% and 85% maximum tumour dose was 178 ml (median 183 ml; range 89-244 ml) and 110 ml (median 110 ml; 40-179 ml) respectively. This represents an average reduction of 13% and 8% of normal brain volume. Although clinically important this may not be sufficient for a significant improvement in therapeutic ratio.