Catharine H. Clark

Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial

Summary Background Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. Methods We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1–4, N0–3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. Findings 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0–59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56–87] of 34 patients given conventional radiotherapy vs 15 [38%; 23–55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23–61] of 44 patients given conventional radiotherapy vs 35 [74%; 55–89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63–95] of 24 patients given conventional radiotherapy vs nine [29%; 14–48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. Interpretation Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. Funding Cancer Research UK (CRUK/03/005).

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial

BACKGROUND Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. METHODS We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3-6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. FINDINGS 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5-61·3), six (4·3%; 95% CI 1·6-9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2-8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2-5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5-6·2) of 138 men, three (2·2%; 0·5-6·3) of 137, and none (0·0%; 97·5% CI 0·0-2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. INTERPRETATION Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. FUNDING Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

Volumetric modulated arc therapy: a review of current literature and clinical use in practice

Volumetric modulated arc therapy (VMAT) is a novel radiation technique, which can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques. VMAT also has the potential to offer additional advantages, such as reduced treatment delivery time compared with conventional static field intensity modulated radiotherapy (IMRT). The clinical worldwide use of VMAT is increasing significantly. Currently the majority of published data on VMAT are limited to planning and feasibility studies, although there is emerging clinical outcome data in several tumour sites. This article aims to discuss the current use of VMAT techniques in practice and review the available data from planning and clinical outcome studies in various tumour sites including prostate, pelvis (lower gastrointestinal, gynaecological), head and neck, thoracic, central nervous system, breast and other tumour sites.

A comparison of the gamma index analysis in various commercial IMRT/VMAT QA systems.

PURPOSE To investigate the variability of the global gamma index (γ) analysis in various commercial IMRT/VMAT QA systems and to assess the impact of measurement with low resolution detector arrays on γ. MATERIALS Five commercial QA systems (PTW 2D-Array, Scandidos Delta4, SunNuclear ArcCHECK, Varian EPID, and Gafchromic EBT2 film) were investigated. The response of γ analysis to deliberately introduced errors in pelvis and head & neck IMRT and RapidArc™ plans was evaluated in each system. A theoretical γ was calculated in each commercial QA system software (PTW Verisoft, Delta4 software, SNC Patient, Varian Portal Dosimetry and IBA OmniPro, respectively), using treatment planning system resolution virtual measurements and compared to an independent calculation. Error-induced plans were measured on a linear accelerator and were evaluated against the error-free dose distribution calculated using Varian Eclipse™ in the relevant phantom CT scan. In all cases, global γ was used with a 20% threshold relative to a point selected in a high dose and low gradient region. The γ based on measurement was compared against the theoretical to evaluate the response of each system. RESULTS There was statistically good agreement between the predicted γ based on the virtual measurements from each software (concordance correlation coefficient, ρc>0.92) relative to the independent prediction in all cases. For the actual measured data, the agreement with the predicted γ reduces with tightening passing criteria and the variability between the different systems increases. This indicates that the detector array configuration and resolution have greater impact on the experimental calculation of γ due to under-sampling of the dose distribution, blurring effects, noise, or a combination. CONCLUSIONS It is important to understand the response and limitations of the gamma index analysis combined with the equipment in use. For the same pass-rate criteria, different devices and software combinations exhibit varying levels of agreement with the predicted γ analysis.

Dosimetry audit for a multi-centre IMRT head and neck trial

BACKGROUND AND PURPOSE PARSPORT was a multi-centre randomised trial in the UK which compared Intensity-Modulated Radiotherapy (IMRT) and conventional radiotherapy (CRT) for patients with head and neck cancer. The dosimetry audit goals were to verify the plan delivery in participating centres, ascertain what tolerances were suitable for head and neck IMRT trials and develop an IMRT credentialing program. MATERIALS AND METHODS Centres enrolling patients underwent rigorous quality assurance before joining the trial. Following this each centre was visited for a dosimetry audit, which consisted of treatment planning system tests, fluence verification films, combined field films and dose point measurements. RESULTS Mean dose point measurements were made at six centres. For the primary planning target volume (PTV) the differences with the planned values for the IMRT and CRT arms were -0.6% (1.8% to -2.4%) and 0.7% (2.0% to -0.9%), respectively. Ninety-four percent of the IMRT fluence films for individual fields passed gamma criterion of 3%/3mm and 75% of the films for combined fields passed gamma criterion 4%/3mm (no significant difference between dynamic delivery and step and shoot delivery). CONCLUSIONS This audit suggests that a 3% tolerance could be applied for PTV point doses. For dose distributions tolerances of 3%/3mm on individual fields and 4%/3mm for combined fields are proposed for multi-centre head and neck IMRT trials.

Dose to bone marrow using IMRT techniques in prostate cancer patients

Purpose:To investigate the dose distribution in active bone marrow of patients undergoing intensity-modulated radiotherapy (IMRT) for prostate cancer and compare it to the distribution in the same patients, if they had been treated using conformal plans, in order to develop criteria for optimization to minimize the estimated risk of secondary leukemia.Patients and Methods:Mean bone marrow doses were calculated for ten patients with localized prostate cancer who underwent whole-pelvis IMRT and compared to three-dimensional conformal (3-D CRT) plans prepared for the same patients. Also for comparison, the IMRT and 3-D CRT plans were produced to simulate the treatment of the prostate gland only. To measure the dose to extrapelvic bone marrow, three thermoluminescent diode (TLD) chips were placed in the middle of the sternum region inside the Rando phantom.Results:For both the pelvic and prostate-only volumes, the IMRT plans were superior to 3-D CRT plans in reducing the high dose volume to the rectum, the bladder and the small bowel while maintaining acceptable coverage of the planning target volume (PTV). For the pelvic treatment group the IMRT plans, compared to 3-D CRT, reduced the high dose volume (> 20 Gy) to os coxae, which is the main contributor of dose to pelvic bone marrow, but increased the middle dose volume (10–20 Gy). No statistically significant differences were observed for lower dose volumes (< 5 Gy). For the prostate-only treatment the IMRT plan increased the high dose volume and slightly decreased the low dose volume of pelvic bone marrow. However, for both treatments the leakage dose to extrapelvic sites was higher by a factor of 2 in IMRT plans.Conclusion:There are significant differences in the dose-volume histograms of bone marrow doses from 3-D CRT and from IMRT. Pronounced dose inhomogeneity reduces the risk of leukemia compared to homogeneous radiation exposure of the bone marrow. The mean bone marrow dose is therefore not a useful criterion to judge plan quality, since scattered low doses to distant sites may be more critical than the high dose volumes receiving > 10 Gy. The number of monitor units needed to deliver an IMRT plan affects leakage dose and their incorporation into planning constraints should be considered.Ziel:Die Dosisverteilung im roten Knochenmark von Patienten, die wegen eines Prostatakarzinoms mit einer intensitätsmodulierten Strahlentherapie (IMRT) behandelt werden, sollte mit derjenigen verglichen werden, die sie bei einer dreidimensionalen (3-D) konformalen Strahlentherapie erhalten würden, um Optimierungskriterien für die Beurteilung von Bestrahlungsplänen zu entwickeln und so das mögliche Risiko einer strahlentherapieinduzierten Leukämie zu minimieren.Patienten und Methodik:Bei zehn Patienten, die eine IMRT des ganzen Beckens erhielten, wurde die Dosisverteilung im roten Knochenmark berechnet und mit der Dosisverteilung verglichen, die sie bei einer 3-D-konformalen Strahlentherapie des gleichen Zielvolumens erhalten hätten. Außerdem wurden die Dosisverteilungen im roten Knochenmark bei ausschließlicher Bestrahlung der Prostata verglichen. Die Dosis außerhalb des Beckens wurde für alle Bestrahlungspläne im Sternum eines Rando-Phantoms mit Thermolumineszenzdioden-(TLD-)Dosimetern gemessen.Ergebnisse:Sowohl bei Bestrahlung des ganzen Beckens als auch der Prostata allein ergab die IMRT-Technik eine Verkleinerung des Hochdosisvolumens im Rektum, in der Blase und im Dünndarm bei akzeptabler Dosisverteilung im Planungszielvolumen (PTV). Die IMRT-Technik reduzierte bei Bestrahlung des Beckens das mit hoher Dosis belastete Knochenmarkvolumen, vergrößerte aber das mit mittlerer Dosis von 10–20 Gy belastete Volumen, während kein Unterschied im mit < 5 Gy belasteten Volumen gemessen wurde. Bei Bestrahlung der Prostata allein vergrößerte die IMRT-Technik das Hochdosisvolumen und verkleinerte das Niedrigdosisvolumen im Becken. Die Leckagedosis war bei der IMRT-Technik um den Faktor 2 erhöht.Schlussfolgerung:Die Dosis-Volumen-Histogramme im roten Knochenmark unterscheiden sich signifikant bei der IMRT im Vergleich zur 3-D-konformalen Strahlentherapie des Prostatakarzinoms. Das durch Bestrahlung ausgelöste Leukämierisiko ist bei ausgeprägter Dosisinhomogenität im Knochenmark geringer als bei homogener Strahlenexposition. Deshalb ist die mittlere Knochenmarkdosis kein geeignetes Kriterium zur Beurteilung von Bestrahlungsplänen, denn Streustrahlendosen in entfernteren Knochenmarkvolumina sind kritischer zu bewerten als Knochenmarkbelastungen von > 10 Gy. Die Zahl der Monitoreinheiten hat einen großen Einfluss auf die Leckagedosis bei der IMRT; es wäre zu überlegen, ob dieser Parameter in die Optimierungskriterien der IMRT einbezogen werden sollte.

Dosimetric explanations of fatigue in head and neck radiotherapy: An analysis from the PARSPORT Phase III trial

BACKGROUND An unexpected finding from the phase III parotid sparing radiotherapy trial, PARSPORT (ISRCTN48243537, CRUK/03/005), was a statistically significant increase in acute fatigue for those patients who were treated with intensity-modulated radiotherapy (IMRT) compared to standard conventional radiotherapy (CRT). One possible explanation was the difference in dose to central nervous system (CNS) structures due to differing beam portals. Using data from the trial, a dosimetric analysis of individual CNS structures was performed. METHOD Dosimetric and toxicity data were available for 67 patients (27 CRT, 40 IMRT). Retrospective delineation of the posterior fossa, brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia was performed. Dosimetry was reviewed using summary statistics and dose-volume atlases. RESULTS A statistically significant increase in maximum and mean doses to each structure was observed for patients who received IMRT compared to those who received CRT. Both maximum and mean doses were significantly higher for the posterior fossa, brainstem and cerebellum for the 42 patients who reported acute fatigue of Grade 2 or higher (p ≤ 0.01) compared to the 25 who did not. Dose-volume atlases of the same structures indicated that regions representing larger volumes and higher doses to each structure were consistent with a higher incidence of acute fatigue. There was no association between the dose distribution and acute fatigue for the other structures tested. CONCLUSIONS The excess fatigue reported in the IMRT arm of the trial may, at least in part, be attributed to the dose distribution to the posterior fossa, cerebellum and brainstem. Future studies that modify dose delivery to these structures may allow us to test the hypothesis that radiation-induced fatigue is avoidable.

IMRT clinical implementation: Prostate and pelvic node irradiation using Helios and a 120-leaf multileaf collimator

Dynamic intensity modulated radiation therapy (IMRT) to treat prostate and pelvic nodes using the Varian 120‐leaf Millennium multileaf collimator (MLC) has been implemented in our clinic. This paper describes the procedures that have been undertaken to achieve this, including some of the commissioning aspects of Helios, verification of the dynamic dose delivery, and quality assurance (QA) of the dose delivered to the patient. Commissioning of Helios included measurements of transmission through the 120‐leaf MLC, which were found to be 1.7% for 6 mV and 1.8% for 10 MV. The rounded leaf edge effect, known as the dosimetric separation, was also determined using two independent methods. Values of 1.05 and 1.65 mm were obtained for 6 and 10 MV beams. Five test patients were planned for prostate and pelvic node irradiation to 70 and 50 Gy, respectively. Dose and fluence verification were carried out on specially designed phantoms and dose points in the prostate were measured to be within 2.0% (mean 0.9%, s.d. 0.6%) of the calculated dose and in the nodes within 3.0% (mean 1.6%, s.d. 1.1%). Following the results of this commissioning and implementation study, we have started to treat men with a target volume including the prostate and pelvic nodes using Helios optimized dynamic IMRT delivery in a dose escalation protocol. PACS number(s): 87.53.–j, 87.90.+y

A multi-institutional dosimetry audit of rotational intensity-modulated radiotherapy

BACKGROUND Rotational IMRT (VMAT and Tomotherapy) has now been implemented in many radiotherapy centres. An audit to verify treatment planning system modelling and treatment delivery has been undertaken to ensure accurate clinical implementation. MATERIAL AND METHODS 34 institutions with 43 treatment delivery systems took part in the audit. A virtual phantom planning exercise (3DTPS test) and a clinical trial planning exercise were planned and independently measured in each institution using a phantom and array combination. Point dose differences and global gamma index (γ) were calculated in regions corresponding to PTVs and OARs. RESULTS Point dose differences gave a mean (±sd) of 0.1±2.6% and 0.2±2.0% for the 3DTPS test and clinical trial plans, respectively. 34/43 planning and delivery combinations achieved all measured planes with >95% pixels passing γ<1 at 3%/3mm and rose to 42/43 for clinical trial plans. A statistically significant difference in γ pass rates (p<0.01) was seen between planning systems where rotational IMRT modelling had been designed for the manufacturers own treatment delivery system and those designed independently of rotational IMRT delivery. CONCLUSIONS A dosimetry audit of rotational radiotherapy has shown that TPS modelling and delivery for rotational IMRT can achieve high accuracy of plan delivery.

Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

PURPOSE To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). METHODS AND MATERIALS A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. RESULTS Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. CONCLUSIONS At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study.