R. Jena

Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma

BackgroundThe cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.MethodsFour human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888′s PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus.ResultsCombining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells.ConclusionsThis study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.

Advances in radiotherapy

#### 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 …

Residual Postoperative Tumour Volume Predicts Outcome after High-dose Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine

AIMS High-dose radiotherapy after surgical debulking is the treatment of choice for chordomas and chondrosarcomas. This study reviewed our outcomes, in relation to residual tumour volume and radiation dose, in order to inform our future practice. PATIENTS AND METHODS Nineteen patients referred to the Neuro-Oncology Unit at Addenbrookes Hospital (Cambridge, UK) between 1996 and 2009 and treated with photon radiotherapy were reviewed. Seventeen of the 19 were treated with curative intent. The median follow-up was 53 months. The tumours in the study had a mean gross tumour volume (GTV) of 17.2 cm(3) (median 10.5 cm(3)) and a range of 0-76.3 cm(3). The median dose was 65Gy in 39 fractions. RESULTS The 5 year cause-specific survival for radically treated patients with chordomas was 92% and the 5 year local control rate was 83%. The 5 year cause-specific survival and local control rates with chondrosarcomas were both 100%. A planning target volume (PTV) below 90 cm(3) is predictive of local control, but volumes above this are not. The GTV seems to be a better predictor of outcome: among the 17 of 19 patients treated curatively, a GTV threshold of 30 cm(3) distinguished local failures from the 15 patients with local control, with sensitivity to detect local control of 100% (95% confidence interval 78-100%), specificity 100% (95% confidence interval 16-100%) and positive predictive value 100% (95% confidence interval 78-100%). CONCLUSIONS Our results show a high level of efficacy for fractionated photon radiotherapy after surgery, in keeping with other series. In addition, we found that although surgical debulking is essential, a small residual tumour volume may still be controlled with high-dose photon radiotherapy. This information may be relevant during neurosurgical planning, possibly allowing a reduction in risk of serious neurological deficits. This should encourage the further development of sophisticated photon radiotherapy, for patients unsuitable for proton therapy.

Tumour bed delineation for partial breast/breast boost radiotherapy: What is the optimal number of implanted markers?

PURPOSE International consensus has not been reached regarding the optimal number of implanted tumour bed (TB) markers for partial breast/breast boost radiotherapy target volume delineation. Four common methods are: insertion of 6 clips (4 radial, 1 deep and 1 superficial), 5 clips (4 radial and 1 deep), 1 clip at the chest wall, and no clips. We compared TB volumes delineated using 6, 5, 1 and 0 clips in women who have undergone wide-local excision (WLE) of breast cancer (BC) with full-thickness closure of the excision cavity, in order to determine the additional margin required for breast boost or partial breast irradiation (PBI) when fewer than 6 clips are used. METHODS Ten patients with invasive ductal BC who had undergone WLE followed by implantation of six fiducial markers (titanium clips) each underwent CT imaging for radiotherapy planning purposes. Retrospective processing of the DICOM image datasets was performed to remove markers and associated imaging artefacts, using an in-house software algorithm. Four observers outlined TB volumes on four different datasets for each case: (1) all markers present (CT6M); (2) the superficial marker removed (CT(5M)); (3) all but the chest wall marker removed (CTCW); (4) all markers removed (CT(0M)). For each observer, the additional margin required around each of TB(0M), TBCW, and TB(5M) in order to encompass TB(6M) was calculated. The conformity level index (CLI) and differences in centre-of-mass (COM) between observers were quantified for CT(0M), CTCW, CT(5M), CT(6M). RESULTS The overall median additional margins required to encompass TB(6M) were 8mm (range 0-28 mm) for TB(0M), 5mm (range 1-13 mm) for TBCW, and 2mm (range 0-7 mm) for TB(5M). CLI were higher for TB volumes delineated using CT(6M) (0.31) CT(5M) (0.32) than for CTCW (0.19) and CT(0M) (0.15). CONCLUSIONS In women who have undergone WLE of breast cancer with full-thickness closure of the excision cavity and who are proceeding to PBI or breast boost RT, target volume delineation based on 0 or 1 implanted markers is not recommended as large additional margins are required to account for uncertainty over true TB location. Five implanted markers (one deep and four radial) are likely to be adequate assuming the addition of a standard 10-15 mm TB-CTV margin. Low CLI values for all TB volumes reflect the sensitivity of low volumes to small differences in delineation and are unlikely to be clinically significant for TB(5M) and TB(6M) in the context of adequate TB-CTV margins.

Radiotherapy Demand and Activity in England 2006–2020

AIMS This paper compares the predictions of radiotherapy demand for England from the Malthus model with those from the earlier National Radiotherapy Advisory Group (NRAG) model, from the international literature and also with observed radiotherapy usage in England as a whole as recorded in the English radiotherapy dataset (RTDS). MATERIALS AND METHODS We reviewed the evidence base for radiotherapy for each type and stage of cancer using national and international guidelines, meta-analyses, systematic reviews and key clinical trials. Twenty-two decision trees were constructed and radiotherapy demand was calculated using English cancer incidence data for 2007, 2008 and 2009, accurate to the Primary Care Trust (PCT) level (population 91,500-1,282,384). The stage at presentation was obtained from English cancer registry data. In predictive mode, the model can take account of changes in cancer incidence as the population grows and ages. RESULTS The Malthus model indicates reduced indications for radiotherapy, principally for lung cancer and rarer tumours. Our estimate of the proportion of patients who should receive radiotherapy at some stage of their illness is 40.6%. This is lower than previous estimates of about 50%. Nevertheless, the overall estimate of demand in terms of attendances is similar for the NRAG and Malthus models. The latter models that 48,827 attendances should have been delivered per million population in 2011. National data from RTDS show 32,071 attendances per million in 2011. A 50% increase in activity would be required to match estimated demand. This underprovision extends across all cancers and represents reduced access and the use of dose fractionation at odds with international norms of evidence-based practice. By 2016, demand is predicted to grow to about 55,206 attendances per million and by 2020 to 60,057. DISCUSSION Services have increased their activity by 14% between 2006 and 2011, but estimated demand has increased by 11%. Access remains low and English radiotherapy dose fractionation still does not comply with international evidence-based practice.

Excellent Local Control of Paraganglioma in the Head and Neck with Fractionated Radiotherapy

AIMS Radiotherapy is an important treatment option for paraganglioma in the head and neck region. It seems to be highly effective and avoids important surgical morbidity, which can impair quality of life. The aim of this study was to evaluate the outcomes of radiotherapy for paraganglioma of the head and neck region in order to inform our future practice. MATERIALS AND METHODS The cohort of patients for the present study comprised 21 patients who received radiotherapy between 1998 and 2008. Follow-up ranged from 6 to 132 months, median 55 months. The mean age was 48.7 years, range 20-78 years. The female:male ratio was 2 : 1. Two patients had confirmed familial tumour syndromes. The gross tumour volume in 20 cases ranged from 1.3 to 74 cm(3), mean 23.2 cm(3), median 14.7 cm(3). Five patients were treated with intensity-modulated radiotherapy. The median dose was 50 Gy in 30 fractions. RESULTS The crude 5-year local control rate was 95% (20/21), although the 5-year actuarial local control rate was 87%. The one patient who relapsed, at 45 months after radiotherapy, had a comparatively small tumour of 10.8 cm(3). A relationship between tumour volume and local control seems unlikely. It was possible to obtain details of side-effects from electronic records for 11 patients. Grade 3 headache, which resolved, was the most serious acute side-effect. One patient had three teeth extracted due to exacerbation of dental caries, and one had deterioration of hearing thought to be due to a combination of tumour and radiotherapy. There were two serious complications in patients who had embolisation, which we no longer use. CONCLUSIONS Our results show a high level of efficacy for fractionated external beam radiotherapy, with minimal toxicity, in keeping with other series. This should encourage the use of radiotherapy as primary treatment for paragangliomas of the head and neck region.

The Malthus Programme — A New Tool for Estimating Radiotherapy Demand at a Local Level

The radiotherapy delivery service in England is emerging from a 25 year blight on strategic planning and forecasting of radiotherapy demand. Two of the most influential documents used as evidence for renovation and expansion in radiotherapy services are the Royal College of Radiologists (RCR) equipment, workload and staffing survey [1] and the National Radiotherapy Advisory Group (NRAG) report [2]. Where the RCR survey quantified significant variation in allocation and consumption of radiotherapy resources across England and Wales, the NRAG 2007 report generated national targets for radiotherapy service provision in terms of fraction burden (40,000 fractions per million of population by 2010 and up to 54,000 fractions per million by 2016) and the proportion of cancer patients receiving radiotherapy at some point in their cancer journey (access rate), which was estimated at 52% [3]. Although the NRAG model has been instrumental in providing evidence of radiotherapy under provision, it has proven difficult for clinicians and local commissioning groups to apply the model at a regional level, just as the RCR report would have predicted. Independent of any differences in clinical practice among radiation oncologists across the country, local variation in radiotherapy demand is driven by differences in population demographics and age distribution, co-morbidity, disease incidence and variation in the diagnostic and surgical pathways leading to radiotherapy treatment. It clear that a national ‘best fit’ model cannot provide a good fit for commissioning and service provision at the local level.

Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment

The recent advances in radiation delivery can improve tumour control probability (TCP) and reduce treatment-related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally, IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day to day. Daily image guidance scans can be used to identify the position of normal tissue structures and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues that limits radiotherapy (RT) dose and therefore tumour control. However, the dose–response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of RT. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be owing to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In patients with prostate cancer receiving curative RT, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses was −2.7 Gy (5%), and a dose reduction was seen in 7 of the 10 cases. If dose escalation was performed to take rectal dose back to the planned level, this should increase the mean TCP (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical RT who might benefit from either dose escalation, suggesting improved tumour cure or reduced toxicity or both.

Correlation of a hypoxia based tumor control model with observed local control rates in nasopharyngeal carcinoma treated with chemoradiotherapy.

PURPOSE To extend the application of current radiation therapy (RT) based tumor control probability (TCP) models of nasopharyngeal carcinoma (NPC) to include the effects of hypoxia and chemoradiotherapy (CRT). METHODS A TCP model is described based on the linear-quadratic model modified to account for repopulation, chemotherapy, heterogeneity of dose to the tumor, and hypoxia. Sensitivity analysis was performed to determine which parameters exert the greatest influence on the uncertainty of modeled TCP. On the basis of the sensitivity analysis, the values of specific radiobiological parameters were set to nominal values reported in the literature for NPC or head and neck tumors. The remaining radiobiological parameters were determined by fitting TCP to clinical local control data from published randomized studies using both RT and CRT. Validation of the model was performed by comparison of estimated TCP and average overall local control rate (LCR) for 45 patients treated at the institution with conventional linear-accelerator-based or helical tomotherapy based intensity-modulated RT and neoadjuvant chemotherapy. RESULTS Sensitivity analysis demonstrates that the model is most sensitive to the radiosensitivity term alpha and the dose per fraction. The estimated values of alpha and OER from data fitting were 0.396 Gy(-1) and 1.417. The model estimate of TCP (average 90.9%, range 26.9%-99.2%) showed good correlation with the LCR (86.7%). CONCLUSIONS The model implemented in this work provides clinicians with a useful tool to predict the success rate of treatment, optimize treatment plans, and compare the effects of multimodality therapy.

Random variation in rectal position during radiotherapy for prostate cancer is two to three times greater than that predicted from prostate motion

Objective: Radiotherapy for prostate cancer does not explicitly take into account daily variation in the position of the rectum. It is important to accurately assess accumulated dose (DA) to the rectum in order to understand the relationship between dose and toxicity. The primary objective of this work was to quantify systematic (Σ) and random (σ) variation in the position of the rectum during a course of prostate radiotherapy. Methods: The rectum was manually outlined on the kilo-voltage planning scan and 37 daily mega-voltage image guidance scans for 10 participants recruited to the VoxTox study. The femoral heads were used to produce a fixed point to which all rectal contours were referenced. Results: Σ [standard deviation (SD) of means] between planning and treatment was 4.2 mm in the anteroposterior (AP) direction and 1.3 mm left–right (LR). σ (root mean square of SDs) was 5.2 mm AP and 2.7 mm LR. Superior–inferior variation was less than one slice above and below the planning position. Conclusion: Our results for Σ are in line with published data for prostate motion. σ, however, was approximately twice as great as that seen for prostate motion. This suggests that DA may differ from planned dose in some patients treated with radiotherapy for prostate cancer. Advances in knowledge: This work is the first to use daily imaging to quantify Σ and σ of the rectum in prostate cancer. σ was found to be greater than published data, providing strong rationale for further investigation of individual DA.