E. Miles

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).

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.

Pre-trial quality assurance processes for an intensity-modulated radiation therapy (IMRT) trial: PARSPORT, a UK multicentre Phase III trial comparing conventional radiotherapy and parotid-sparing IMRT for locally advanced head and neck cancer

The purpose of this study was to compare conventional radiotherapy with parotid gland-sparing intensity-modulated radiation therapy (IMRT) using the PARSPORT trial. The validity of such a trial depends on the radiotherapy planning and delivery meeting a defined standard across all centres. At the outset, many of the centres had little or no experience of delivering IMRT; therefore, quality assurance processes were devised to ensure consistency and standardisation of all processes for comparison within the trial. The pre-trial quality assurance (QA) programme and results are described. Each centre undertook exercises in target volume definition and treatment planning, completed a resource questionnaire and produced a process document. Additionally, the QA team visited each participating centre. Each exercise had to be accepted before patients could be recruited into the trial. 10 centres successfully completed the quality assurance exercises. A range of treatment planning systems, linear accelerators and delivery methods were used for the planning exercises, and all the plans created reached the standard required for participation in this multicentre trial. All 10 participating centres achieved implementation of a comprehensive and robust IMRT programme for treatment of head and neck cancer.

Intensity-modulated radiotherapy allows escalation of the radiation dose to the pelvic lymph nodes in patients with locally advanced prostate cancer: preliminary results of a phase I dose escalation study

AIM Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy. MATERIALS AND METHODS Eligible patients had high-risk (T3, Gleason > or =8 or prostate-specific antigen > or =20 ng/ml) or lymph node-positive disease. Intensity-modulated radiotherapy was inverse planned giving 70 Gy/35 fractions to the prostate and 50 Gy/55 Gy/60 Gy in sequential cohorts to the pelvis with a 5 Gy boost to positive lymph nodes. Acute and late toxicity were recorded with Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue - Subjective Objective Management LENT-SOM scales. Neoadjuvant androgen suppression was given for 3 years. This report concerns the 50 and 55 Gy cohorts. RESULTS Seventy-nine men were recruited (25 to 50 Gy/54 to 55 Gy) with a median follow-up of 2 years. Patients were divided into two groups according to the total bowel volume outlined (median 450 cm(3)). Acute RTOG (> or =2) bowel toxicity was 40 and 50% for the 50 and 55 Gy groups and 38 and 51% for bowel volume <450 cm(3) and > or =450 cm(3), respectively, suggesting both volume and dose relationships for acute effects. Late RTOG diarrhoea > or =grade 2 was only seen with bowel volume > or =450 cm(3), but no dose effect was apparent (12%/50 Gy and 10%/55 Gy). LENT-SOM bowel > or =grade 2 toxicity occurred in 22%/50 Gy and 15%/55 Gy. Only one patient had grade 3 toxicity. A dose volume histogram analysis showed increased late RTOG diarrhoea > or =grade 2 with larger bowel volume irradiated, significant for BV40 >124 cm(3) (P=0.04), BV45 >71 cm(3) (P=0.03) and BV60 >2 cm(3) (P=0.01). CONCLUSIONS Acute and late bowel toxicity was acceptably low using a pelvic dose of up to 55 Gy over 7 weeks. Both relate to total pelvic bowel volume and dose volume constraints have been defined.

NIMRAD – A Phase III Trial to Investigate the Use of Nimorazole Hypoxia Modification with Intensity-modulated Radiotherapy in Head and Neck Cancer

NIMRAD is a randomised placebo-controlled trial of synchronous nimorazole versus radiotherapy alone in patients with locally advanced head and neck oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma not suitable for synchronous chemotherapy or cetuximab. Eighteen UK centres aim to recruit a total of 470 patients over the next 4 years. The trial aims are to: (i) assess the benefit of hypoxia modification in those unsuitable for standard synchronous systemic therapies, including elderly or less fit patients; (ii) determine the effectiveness and tolerability of synchronous nimorazole when used with contemporary advanced radiotherapy techniques (fixed beam or rotational intensity-modulated radiotherapy, IMRT); (iii) validate a hypoxia gene signature for use in the clinic as a predictive biomarker; and (iv) standardise the UK approach to the definition of head and neck IMRT treatment volumes. A radiotherapy quality assurance programme for head and neck volume delineation and IMRT treatment planning has been specifically developed for NIMRAD, which aims to maintain the quality of treatment delivery while minimising quality assurance repetition. Locally Advanced Head and Neck Squamous Cell Carcinoma

Improving radiotherapy quality assurance in clinical trials: assessment of target volume delineation of the pre-accrual benchmark case

As the complexity of radiotherapy (RT) trials increases, issues surrounding target volume delineation will become more important. Some form of outlining assessment prior to trial entry is increasingly being mandated in UK RT trials. This document produced by the Outlining and Imaging Subgroup (OISG) of the National Cancer Research Institute will address methods to reduce interobserver variation in clinical trials and how to conduct an assessment of outlining through a pre-accrual benchmark case. We review currently available methods of describing the variation and identify areas where further work is needed. The OISG would encourage ongoing discussion with chief investigators in order to provide advice on individual aspects of benchmark case assessment for current and future trials.

Radiotherapy dosimetry audit: three decades of improving standards and accuracy in UK clinical practice and trials

Dosimetry audit plays an important role in the development and safety of radiotherapy. National and large scale audits are able to set, maintain and improve standards, as well as having the potential to identify issues which may cause harm to patients. They can support implementation of complex techniques and can facilitate awareness and understanding of any issues which may exist by benchmarking centres with similar equipment. This review examines the development of dosimetry audit in the UK over the past 30 years, including the involvement of the UK in international audits. A summary of audit results is given, with an overview of methodologies employed and lessons learnt. Recent and forthcoming more complex audits are considered, with a focus on future needs including the arrival of proton therapy in the UK and other advanced techniques such as four-dimensional radiotherapy delivery and verification, stereotactic radiotherapy and MR linear accelerators. The work of the main quality assurance and auditing bodies is discussed, including how they are working together to streamline audit and to ensure that all radiotherapy centres are involved. Undertaking regular external audit motivates centres to modernize and develop techniques and provides assurance, not only that radiotherapy is planned and delivered accurately but also that the patient dose delivered is as prescribed.

Radiation therapy quality assurance in clinical trials – Global harmonisation group

Participation in large multi-centre clinical trials aids establishment of the safety and efficacy of new cancer treatments and methods. Oncology clinical trials have contributed to improved local control, overall survival and quality of life for patients with varying disease types [1]. Radiation Therapy is indicated in the course of treatment for more than 50% of all cancer patients [2,3] and consequently a high percentage of oncology clinical trials include radiotherapy within their treatment schema. Collaboration between global clinical trial groups and organisations has increased the number of patient records available for analysis permitting faster recruitment [4], broader acceptance and wider impact of trial results. Global cooperation is also essential in the environment of rare cancers [5], in order to be able to create sufficiently large patient data sets within a reasonable recruitment period. A successful example is the EORTC 26981/National Cancer Institute of Canada (NCIC) CE3 intergroup trial, where 573 Glioblastoma patients were randomised within 20 months [6], despite the low prevalence of the disease among the general population. Globally, clinical trial groups and organisations have independently implemented their own Radiation Therapy (RT) Quality Assurance (QA) programs within their corresponding large multicentre clinical trials. Various trial groups have reported that the implementation of RTQA procedures enhanced protocol compliance [7–13]. In four Radiation Therapy Oncology Group (RTOG) studies compliance with the study protocol was enhanced by incorporating pre-treatment review of RT planning [8]. A Trans-Tasman Radiation Oncology Group (TROG) QA audit identified a reduction in unacceptable protocol violations due to three main factors, among which was the QA procedure itself [7]. More recently, strict RTQA procedures have been shown by TROG to have impacted on both trial protocol compliance as well as general clinical practice in prostate RT [9]. For several EORTC studies it has been shown that centres which previously participated in a Dummy Run (DR) were significantly more likely to be successful at subsequent DR attempts and delivery of protocol-compliant RT [10]. Additionally, the impact of RTQA on actual clinical trial outcome has been recently demonstrated in the setting of various cancer sites [11], stressing its importance and correlation with survival [12,13]. However, the various approaches as to how RTQA in clinical trials is performed, evaluated and described are diverse, making analysis and inter-trial comparisons of RTQA results challenging. This hampers cooperation between trial groups and impedes the exchange and interpretation of RTQA data. The costs of running an RTQA program have also increased with the introduction of new advanced technologies. This increases the need to make RTQA more efficient and streamline the QA workload demanded of clinical centres recruiting into international trials [14,15]. As shown by Pettersen et al [4] these RTQA efforts can potentially reduce the number of patients required for trials which could lead to further substantial savings and faster availability of results. The need for a global forum on harmonisation of RTQA within clinical trials thus became apparent. After initial discussions in Goteborg during ESTRO 27 in 2008 the Global Clinical Trials RTQA Harmonisation Group (GHG) was formally established in 2010. The goals of the GHG are: Collate, homogenise and distribute information regarding the RTQA standards of the clinical trial groups, Provide a platform for prospective discussions on new RTQA procedures, software tools, guidelines and policies of trial groups and Provide a framework to endorse existing and future RTQA procedures and guidelines across various trial groups. Each organisation will have the opportunity to endorse RTQA procedures from other organisations and thus accept them much faster in future collaborative trials. In Table 1 the human resources and number of intergroup trials of the steering committee members of the GHG are given. Further information about terms of reference and current and future projects can be found on its website: www.RTQAHarmonisation.org. Table 1 RTQA within each of the current GHG steering committee members as of August 2013. All RTQA groups and organisations participate in international collaborative work to some degree, although there are differences between the USA and all other groups. These differences can be explained by the differences in the funding levels and that most USA RTQA groups only work with NCI funded clinical trials mainly operated in North America [16]. Recently, the North American RTQA organisations have joined forces in the new Imaging and Radiation Oncology Core (IROC) group. The dedicated human resources also vary significantly, most likely due to differences in the QA philosophy of the funding agencies and their commitment to RTQA, although most of the GHG members have at least one Radiation Oncologist, one Medical Physicist and one Radiation Technologist dedicated full time to RTQA. Until now the GHG has contributed to the harmonisation of naming conventions [17], strategies to develop an efficient evidence-based clinical trials RTQA system [14] and the development of a global model for the international recognition of the activities of national and regional Dosimetry Audit Networks [18]. Currently, each trial group has defined its own RTQA procedures [10,19–24] that differ significantly in number, naming conventions and implementation methods [22,25–31]. The GHG is addressing this by collating all RTQA procedures of each member, comparing them and proposing common, harmonised names and procedures. Although RTQA has been proven to be effective, international differences hamper intergroup collaboration. The Global Clinical Trials RTQA Harmonisation Group has been established to reduce those differences, capitalise on the range of expertise available internationally, increase the power of RT clinical trials, deliver consistency in the reporting of trial quality factors and facilitate the undertaking of effective multi-national trials and data analysis. Although important progress has already been made, many challenges remain to be addressed.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

Purpose To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

Prospective review of radiotherapy trials through implementation of standardized multicentre workflow and IT infrastructure

OBJECTIVE: We sought to develop a process that would allow us to perform a prospective review of outlining in trials using expert reviewers based in multiple centres. METHODS: We implemented a specific information technology infrastructure and workflow that could serve all organizations involved in the radiotherapy quality assurance (RTQA) process. RESULTS: Data were processed and packaged in the computational environment for radiotherapy research (CERR) binary format and securely transmitted to the expert reviewer at the designated remote organization. It was opened and reviewed using the distributed CERR-compiled application, and a standardized report was sent to the respective centre. Centres were expected to correct any unacceptable deviations and resubmit outlining for approval prior to commencing treatment. 75% of reviews were completed and fed back to centres within 3 working days. There were no delays in treatment start date. CONCLUSION: Our distributed RTQA review approach provides a method of prospective outlining review at multiple centres, without compromising the quality, delaying the start of treatment or the need for significant additional infrastructure resources. Future progress in the area of prospective individual case review will need to be supported by additional resources for clinician time to undertake the reviews. ADVANCES IN KNOWLEDGE: Trial groups around the world have formulated different approaches to address the need for the prospective review of radiotherapy (RT) data with clinical trials, in line with available resources. We report a UK solution that has allowed the workload for outlining review to be distributed across a wider group of volunteer reviewers without the need for any additional infrastructure costs and has already been adopted within the UK RT trials community.