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Radiotherapy Research Priorities for the UK
... As well as increasing the provision of conventional radiotherapy treatments, there has been increased utilisation of advanced radiotherapy modalities, including image-guided radiotherapy, intensity-modulated radiotherapy and proton beam therapy [15,16]. A common goal is increasing the number of adaptive radiotherapy treatments, defined as 'aiming to customise each patient's treatment plan to patient-specific variation by evaluating and characterizing the systematic and random variations through image feedback and including them in adaptive planning' [17]. ...
Aims
Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England.
Materials and methods
Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England.
Results
Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions.
Conclusions
Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.
... A natural consequence of this process will be the identification of generic and specific targets: the former will apply to a broad range of tumour types (e.g., targeting the DNA damage response) (Helleday et al, 2008) while the latter may only be relevant to a small number of tumours (e.g., EGFR variant III in head and neck cancer and glioblastoma) (Sok et al, 2006; Mukherjee et al, 2009). In order to avoid a piecemeal approach in which some targets are neglected while others are the subject of overlapping research by different groups, there is an urgent need to establish a network of research teams with expertise in molecular radiobiology and the desire to test the potential of targeted drugs to act as radiosensitisers (Maughan et al, 2010). Even with such an initiative, it must be understood that the number of possible targets and the availability of more than one drug for each target dictates the need for consensus guidelines that can be used to aid target selection and prioritisation, preliminary in vitro and in vivo testing and subsequent early phase clinical trials. ...
There is a growing appreciation of the potential value of combining novel molecularly-targeted drugs with radiotherapy or chemoradiotherapy. Such approaches have the potential to improve locoregional disease control and cure rates across a diverse range of tumour types. In this report, we outline a rational framework for developing novel drug-radiation combinations. In doing so, we make recommendations regarding the core preclinical data sets that are required to serve as justification for studies in humans and describe potential clinical trial designs that may be adopted by investigators.
... One outcome of the rapid review was the refashioning of the previous NCRI Radiotherapy Clinical Studies Group into a multistream working group with a substantially broader remit. This new NCRI group, the Clinical and Translational Radiotherapy Research Working Group (CTRad), was launched in July 2009 [3,4]. CTRad has an executive group and four workstreams, focusing on the science base, Phase I/II trials, Phase III trials and methodology, and new technology, including physics and quality assurance (QA). ...
In 2011, the Clinical and Translational Radiotherapy Research Working Group (CTRad) of the National Cancer Research Institute brought together UK radiotherapy physics leaders for a think tank meeting. Following a format that CTRad had previously and successfully used with clinical oncologists, 23 departments were asked to complete a pre-meeting evaluation of their radiotherapy physics research infrastructure and the strengths, weaknesses, opportunities and threats within their own centre. These departments were brought together with the CTRad Executive Group and research funders to discuss the current state of radiotherapy physics research, perceived barriers and possible solutions. In this Commentary, we summarise the submitted materials, presentations and discussions from the meeting and propose an action plan. It is clear that there are challenges in both funding and staffing of radiotherapy physics research. Programme and project funding streams sometimes struggle to cater for physics-led work, and increased representation on research funding bodies would be valuable. Career paths for academic radiotherapy physicists need to be examined and an academic training route identified within Modernising Scientific Careers; the introduction of formal job plans may allow greater protection of research time, and should be considered. Improved access to research facilities, including research linear accelerators, would enhance research activity and pass on developments to patients more quickly; research infrastructure could be benchmarked against centres in the UK and abroad. UK National Health Service departments wishing to undertake radiotherapy research, with its attendant added value for patients, need to develop a strategy with their partner higher education institution, and collaboration between departments may provide enhanced opportunities for funded research.
... It is clear that radiotherapy trials have to be well designed with a relevant clinical question and realistic recruitment targets in order to succeed. In 2009, the National Clinical Research Institute (NCRI) Clinical and Translational Radiotherapy Research Working Group (CTRad) was established with the over-arching remit of improving the quality of UK radiotherapy research [1]. The working group comprises four workstreams: 1: Science base; 2: Phase I/II trials; 3: Phase III trials and methodologies; 4: New technology, physics and quality assurance. ...
One in three people will develop cancer and around half of these will be treated with radiotherapy, with most receiving radical treatment with curative intent (http:// globocan.iarc.fr/factsheets/cancers/all.asp). However, conducting randomised controlled trials addressing radiotherapy questions can be challenging. This editorial will explore solutions to optimise the success of radiotherapy trials,withreferencetolungandbreastradiotherapystudies.
#### Summary points
Radiotherapy plays an important role in the care of patients with cancer and forms part of the management of 40% of patients cured of their disease.1 Advances have been made in the past two decades, as improvements in engineering and computing have enabled technologies such as intensity modulated radiotherapy (IMRT), image guided radiotherapy (IGRT), and stereotactic radiotherapy (SRT) to be used in routine clinical practice.
This article explains newer radiotherapy techniques and aims to enable general practitioners and non-specialist clinicians to advise patients who come to them with questions. It will focus on external beam radiotherapy (EBRT), which is the most common form of treatment, delivered to 125 000 patients a year in England.2
#### Sources and selection criteria
This article is an evidence based review of clinical radiotherapy. We searched PubMed and the Cochrane databases between 1990 and 2012 using the search terms radiotherapy, intensity modulated radiotherapy, image guided radiotherapy, stereotactic radiotherapy, and proton beam therapy to identify observational studies, randomised trials, meta-analyses, and systematic reviews.
X rays are a form of electromagnetic radiation that deliver their energy through waves called photons. These photons are produced by accelerating a stream of electrons and colliding them with a metal target. High energy photons produce secondary electrons in human tissue. Electrons cause DNA damage which, if not repaired, proves fatal at cell division. Absorbed …
delivery systems. It has evolved through simple quality control of treatment machines to verification of the entire radiotherapy process. Quality assurance programmes have become more extensive, anticipating the challenges of evolving technology, and the intensity of individual programmes have been tailored to clinical trial objectives. Comprehensive quality assurance has ultimately enabled centres, supported by the extensive expertise from the RTTQA group, to establish best practice and has played an important role in the adoption of new radiotherapy techniques that then become established within UK practice. UK Evidence for the Implementation of New Techniques Evidence from UK breast trials illustrate changes in breast techniques across recruiting centres in order to comply with the requirements of individual protocols [7,8]. The START trial was instrumental in initiating a standardisation process across breast radiotherapy that would enable future trials to implement more complex radiotherapy on a sound basis [7]. IMPORT LOW has introduced the use of surgical clips to mark the tumour bed; a practice that has now been endorsed by the Association of Breast Surgeons at the British Association of Surgical Oncology [8]. At the start of the Medical Research Council RT01 trial, conformal radiotherapy for prostate cancer was in its infancy. The associated quality assurance programme facilitated conformal radiotherapy implementation across the UK [9]. It was also the first trial to showan improvement in treatment set-up accuracy through its quality assurance programme [10]. The CHHiP trial investigated the use of hypofractionated intensity-modulated radiotherapy (IMRT) schedules for prostate cancer at a time when many UK centres were yet to
Intensity-modulated radiotherapy (IMRT) is a development of three-dimensional conformal radiotherapy that offers improvements in dosimetry in many clinical scenarios. Here we review the clinical evidence for IMRT and present ongoing or unpublished randomised controlled trials (RCTs).
We identified randomised and non-randomised comparative studies of IMRT and conventional radiotherapy using MEDLINE, hand-searching Radiotherapy and Oncology and the International Journal of Radiation Oncology, Biology and Physics and the proceedings of the American Society for Therapeutic Radiology and Oncology and the European Society for Therapeutic Radiology and Oncology annual meetings. The metaRegister of Controlled Trials was searched to identify completed-unpublished, ongoing and planned RCTs.
Sixty-one studies comparing IMRT and conventional radiotherapy were identified. These included three RCTs in head and neck cancer (205 patients) and three in breast cancer (664 patients) that had reported clinical outcomes; these were all powered for toxicity-related end points, which were significantly better with IMRT in each trial. There were 27 additional non-randomised studies in head and neck (1119 patients), 26 in prostate cancer (>5000 patients), four in breast cancer (875 patients) and nine in other tumour sites. The results of these studies supported those of the RCTs with benefits reported in acute and late toxicity, health-related quality of life and tumour control end points. Twenty-eight completed-unpublished, ongoing or planned RCTs incorporating IMRT were identified, including at least 12,310 patients, of which 15 compared conventional radiotherapy within IMRT as a randomisation or pre-planned stratification.
Inverse-planned IMRT maintains parotid saliva production and reduces acute and late xerostomia during radiotherapy for locally advanced head and neck cancer, reduces late rectal toxicity in prostate cancer patients allowing safe dose escalation and seems to reduce toxicity in several other tumour sites. Forward-planned IMRT reduces acute toxicity and improves late clinician-assessed cosmesis compared with conventional tangential breast radiotherapy.
Radiotherapy in the UK lags behind that in much of Europe in terms of both the low proportion of cancer patients gaining access to treatment and the long waiting times [1] and [2]. The technical quality of radiotherapy is also a cause for concern. The National Radiotherapy Advisory Group (NRAG) report published in May 2007 had an overall aim of developing world class radiotherapy [3]. The NRAG technology subgroup report envisaged that within 10 years 50% of patients would be treated by four-dimensional image-guided, adaptive radiotherapy, of which intensity-modulated radiotherapy [IMRT] is a vital component [4]. This paper summarises the work of the National Radiotherapy Implementation Group (NRIG) in supporting the implementation of IMRT.
The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents.
HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non-small cell lung carcinoma (NSCLC) xenografts with biomarker assessment.
Three of six HIV protease inhibitors, nelfinavir, ritonavir, and saquinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 micromol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis.
Nelfinavir is a lead HIV protease inhibitor with pleiotropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration-approved drug that could be repositioned as a cancer therapeutic.
3
Background: TNBC is an aggressive breast cancer subtype that shares molecular and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA repair, and thus represent a rational target of PARP inhibitor-based cancer therapy. The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in combination with gemcitabine/carboplatin (G/C) in subjects with metastatic TNBC. Methods: Eligible subjects had measurable disease and had ≤2 prior cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer. Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000 mg/m ² ) and carboplatin (AUC=2) were given on days 1 and 8, and BSI-201 (5.6 mg/kg; iv; biweekly) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical benefit rate (CBR = CR + PR + SD ≥6 months), progression-free survival (PFS) and overall survival (OS). Results: Analyses of the first 86 of a planned 120 patients showed that BSI-201 + G/C had improved CBR, median PFS, and median OS, compared with G/C alone. The frequency and nature of adverse events (AEs) did not differ between arms. Conclusions: This preliminary analysis demonstrates that BSI-201 + G/C significantly improves CBR, PFS, and OS, compared with G/C alone. BSI-201 + G/C was well tolerated, with BSI-201 adding no significant toxicity to G/C. Updated CBR, PFS, and OS for all 120 patients and exploratory correlative analyses of PARP expression and clinical response will be presented.
[Table: see text] [Table: see text]
Poly(ADP-ribose) polymerases (PARPs) are defined as cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD(+)to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, that presently includes six members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress (oxygen radicals, ionizing radiations and monofunctional alkylating agents). Due to its involvement either in DNA repair or in cell death, PARP-1 is regarded as a double-edged regulator of cellular functions. In fact, when the DNA damage is moderate, PARP-1 participates in the DNA repair process. Conversely, in the case of massive DNA injury, elevated PARP-1 activation leads to rapid NAD(+)/ATP consumption and cell death by necrosis. Excessive PARP-1 activity has been implicated in the pathogenesis of numerous clinical conditions such as stroke, myocardial infarction, shock, diabetes and neurodegenerative disorders. PARP-1 could therefore be considered as a potential target for the development of pharmacological strategies to enhance the antitumor efficacy of radio- and chemotherapy or to treat a number of clinical conditions characterized by oxidative or NO-induced stress and consequent PARP-1 activation. Moreover, the discovery of novel functions for the multiple members of the PARP family might lead in the future to additional clinical indications for PARP inhibitors.
Recent advances in our understanding of the biology of cancer have provided enormous opportunities for the development of novel therapies against specific molecular targets. It is likely that most of these targeted therapies will have only modest single agent activities but may have the potential to accentuate the therapeutic effects of ionising radiation. In this introductory review, the 5Rs of classical radiobiology are interpreted in terms of their relationship to the hallmarks of cancer. Future articles will focus on the specific hallmarks of cancer and will highlight the opportunities that exist for designing new combination treatment regimens.
Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer.
Oral nelfinavir (2 x 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m(2) and 300 mg/m(2) on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m(2). Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected.
At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients.
The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.