Sorting lung tumor volumes from 4D-MRI data using an automatic tumor-based signal reduces stitching artifacts.

PURPOSE: To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D-magnetic resonance (4D-MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor volumes. METHODS: (4D-MRI) scans were collected for 10 lung cancer patients using a 2D T2-weighted single-shot turbo spin echo sequence, obtaining 25 repeat frames per image slice. For each slice, a tumor-motion signal was generated using the first principal component of movement in the tumor neighborhood (TumorPC1). Signals were also generated from displacements of the diaphragm (DIA) and upper and lower chest wall (UCW/LCW) and from slice body area changes (BA). Pearson r coefficients of correlations between observed tumor movement and respiratory signals were determined. TumorPC1, DIA, and UCW signals were used to compile image stacks showing each patient's tumor volume in a respiratory phase. Unsorted image stacks were also built for comparison. For each image stack, the presence of stitching artifacts was assessed by measuring the roughness of the compiled tumor surface according to a roughness metric (Rg). Statistical differences in weighted means of Rg between any two signals were determined using an exact permutation test. RESULTS: The TumorPC1 signal was most strongly correlated with superior-inferior tumor motion, and had significantly higher Pearson r values (median 0.86) than those determined for correlations of UCW, LCW, and BA with superior-inferior tumor motion (p < 0.05). Weighted means of ratios of Rg values in TumorPC1 image stacks to those in unsorted, UCW, and DIA stacks were 0.67, 0.69, and 0.71, all significantly favoring TumorPC1 (p = 0.02-0.05). For other pairs of signals, weighted mean ratios did not differ significantly from one. CONCLUSION: Tumor volumes were smoother in 3D image stacks compiled using the first principal component of tumor motion than in stacks compiled with signals based on normal anatomy.

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Integrated treatment of brain metastases.

PURPOSE OF REVIEW: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has resulted in plethora of publications. We review the existing evidence for individual treatments and new evidence for the integration of systemic and combination of local treatments. RECENT FINDINGS: Encouraging efficacy of systemic therapies supports combination of systemic and local treatment albeit with little randomized trial data. Efficacy particularly of targeted agents provides an opportunity to delay local treatments including radiosurgery and whole brain radiotherapy. Randomized trials testing the integration of surgery, radiotherapy and radiosurgery are reviewed with emphasis on patient relevant endpoints to guide the clinician in the choice and sequence of treatments and integrating systemic and local therapies. SUMMARY: There is increasing tendency to use focused radiation for single and oligometastases with or without surgery and decline in whole brain radiotherapy which is limited to multiple metastases in tumours without effective systemic options. Systemic therapies have promising intracranial efficacy and the sequence and combination with localized radiation is awaiting trials. Changes in practice with a move to primary systemic treatment for brain metastases without radiation, should be undertaken with caution and close monitoring.

Precision oncology: origins, optimism, and potential.

Imatinib, the first and arguably the best targeted therapy, became the springboard for developing drugs aimed at molecular targets deemed crucial to tumours. As this development unfolded, a revolution in the speed and cost of genetic sequencing occurred. The result--an armamentarium of drugs and an array of molecular targets--set the stage for precision oncology, a hypothesis that cancer treatment could be markedly improved if therapies were guided by a tumour's genomic alterations. Drawing lessons from the biological basis of cancer and recent empirical investigations, we take a more measured view of precision oncology's promise. Ultimately, the promise is not our concern, but the threshold at which we declare success. We review reports of precision oncology alongside those of precision diagnostics and novel radiotherapy approaches. Although confirmatory evidence is scarce, these interventions have been widely endorsed. We conclude that the current path will probably not be successful or, at a minimum, will have to undergo substantive adjustments before it can be successful. For the sake of patients with cancer, we hope one form of precision oncology will deliver on its promise. However, until confirmatory studies are completed, precision oncology remains unproven, and as such, a hypothesis in need of rigorous testing.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Radiotherapy for craniopharyngioma.

Radiotherapy remains the mainstay of multidisciplinary management of patients with incompletely resected and recurrent craniopharyngioma. Advances in imaging and radiotherapy technology offer new alternatives with the principal aim of improving the accuracy of treatment and reducing the volume of normal brain receiving significant radiation doses. We review the available technologies, their technical advantages and disadvantages and the published clinical results. Fractionated high precision conformal radiotherapy with image guidance remains the gold standard; the results of single fraction treatment are disappointing and hypofractionation should be used with caution as long term results are not available. There is insufficient data on the use of protons to assess the comparative efficacy and toxicity. The precision of treatment delivery needs to be coupled with experienced infrastructure and more intensive quality assurance to ensure best treatment outcome and this should be carried out within multidisciplinary teams experienced in the management of craniopharyngioma. The advantages of the combined skills and expertise of the team members may outweigh the largely undefined clinical gain from novel radiotherapy technologies.

Improving Outcomes in NSCLC: Optimum Dose Fractionation in Radical Radiotherapy Matters.

INTRODUCTION: We analyzed a comprehensive national radiotherapy data set to compare outcomes of the most frequently used moderate hypofractionation regimen (55 Gy in 20 fractions) and conventional fractionation regimen (60-66 Gy in 30-33 fractions). METHODS: A total of 169,863 cases of NSCLC registered in England from January 2012 to December 2016 obtained from the Public Health England were divided into cohort 1 (training set) diagnosed in 2012 to 2013 and cohort 2 (validation set) diagnosed in 2014 to 2016. Radiotherapy data were obtained from the National Radiotherapy Dataset and linked by National Health Service number to survival data from the Office of National Statistics and Hospital Episode Statistics, from which surgical data and Charlson comorbidity index were obtained. Of 73,186 patients with stages I to III NSCLC, 12,898 received radical fractionated radiotherapy (cohort 1-4894; cohort 2-8004). The proportional hazards model was used to investigate overall survival from time of diagnosis. Survival was adjusted for the prognostic factors of age, sex, stage of disease, comorbidity, other radical treatments, and adjuvant chemotherapy, and the difference between the treatment schedules was summarized by hazard ratio (HR) and 95% confidence interval. The significance of any difference was evaluated by the log likelihood test. RESULTS: Of patients with stages I to III NSCLC, 17% to 18% received radical fractionated radiotherapy. After adjustment for independent prognostic factors of age, stage, comorbidity, and other radical and adjuvant treatments, patients in cohort 1 treated with the 2.75 Gy per fraction regimen had a median survival of 25 months compared with 29 months for patients treated with the 2 Gy per fraction regimen (HR = 1.16, p = 0.001). Similarly, in cohort 2, the respective median survival values were 25 and 28 months (HR = 1.10, p = 0.02). CONCLUSIONS: Big data analysis of a comprehensive national cohort of patients with NSCLC treated in England suggests that compared with a 4-week regimen of 55 Gy in 20 fractions, a 6-week regimen of conventional daily fractionation to a dose of 60 to 66 Gy at 2 Gy per fraction is associated with a survival benefit. Within the limitations of the retrospective big data analysis with potential selection bias and in the absence of randomized trials, the results suggest that conventional fractionation regimens should remain the standard of care.

Cardiac-sparing radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC). MATERIALS AND METHODS: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy). RESULTS: Following re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values. CONCLUSIONS: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.

ESTRO ACROP guideline for target volume delineation of skull base tumors.

BACKGROUND AND PURPOSE: For skull base tumors, target definition is the key to safe high-dose treatments because surrounding normal tissues are very sensitive to radiation. In the present work we established a joint ESTRO ACROP guideline for the target volume definition of skull base tumors. MATERIAL AND METHODS: A comprehensive literature search was conducted in PubMed using various combinations of the following medical subjects headings (MeSH) and free-text words: "radiation therapy" or "stereotactic radiosurgery" or "proton therapy" or "particle beam therapy" and "skull base neoplasms" "pituitary neoplasms", "meningioma", "craniopharyngioma", "chordoma", "chondrosarcoma", "acoustic neuroma/vestibular schwannoma", "organs at risk", "gross tumor volume", "clinical tumor volume", "planning tumor volume", "target volume", "target delineation", "dose constraints". The ACROP committee identified sixteen European experts in close interaction with the ESTRO clinical committee who analyzed and discussed the body of evidence concerning target delineation. RESULTS: All experts agree that magnetic resonance (MR) images with high three-dimensional spatial accuracy and tissue-contrast definition, both T2-weighted and volumetric T1-weighted sequences, are required to improve target delineation. In detail, several key issues were identified and discussed: i) radiation techniques and immobilization, ii) imaging techniques and target delineation, and iii) technical aspects of radiation treatments including planning techniques and dose-fractionation schedules. Specific target delineation issues with regard to different skull base tumors, including pituitary adenomas, meningiomas, craniopharyngiomas, acoustic neuromas, chordomas and chondrosarcomas are presented. CONCLUSIONS: This ESTRO ACROP guideline achieved detailed recommendations on target volume definition for skull base tumors, as well as comprehensive advice about imaging modalities and radiation techniques.

Dyspnea in Patients Receiving Radical Radiotherapy for Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND AND PURPOSE: Dyspnea is an important symptomatic endpoint for assessment of radiation-induced lung injury (RILI) following radical radiotherapy in locally advanced disease, which remains the mainstay of treatment at the time of significant advances in therapy including combination treatments with immunotherapy and chemotherapy and the use of local ablative radiotherapy techniques. We investigated the relationship between dose-volume parameters and subjective changes in dyspnea as a measure of RILI and the relationship to spirometry. MATERIAL AND METHODS: Eighty patients receiving radical radiotherapy for non-small cell lung cancer were prospectively assessed for dyspnea using two patient-completed tools: EORTC QLQ-LC13 dyspnea quality of life assessment and dyspnea visual analogue scale (VAS). Global quality of life, spirometry and radiation pneumonitis grade were also assessed. Comparisons were made with lung dose-volume parameters. RESULTS: The median survival of the cohort was 26 months. In the evaluable group of 59 patients there were positive correlations between lung dose-volume parameters and a change in dyspnea quality of life scale at 3 months (V30 p=0.017; V40 p=0.026; V50 p=0.049; mean lung dose p=0.05), and a change in dyspnea VAS at 6 months (V30 p=0.05; V40 p=0.026; V50 p=0.028) after radiotherapy. Lung dose-volume parameters predicted a 10% increase in dyspnea quality of life score at 3 months (V40; p=0.041, V50; p=0.037) and dyspnea VAS score at 6 months (V40; p=0.027) post-treatment. CONCLUSIONS: Worsening of dyspnea is an important symptom of RILI. We demonstrate a relationship between lung dose-volume parameters and a 10% worsening of subjective dyspnea scores. Our findings support the use of subjective dyspnea tools in future studies on radiation-induced lung toxicity, particularly at doses below conventional lung radiation tolerance limits.

Incidence and evolution of imaging changes on cone-beam CT during and after radical radiotherapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: Cone beam CT (CBCT) is used to improve accuracy of radical radiotherapy by adjusting treatment to the observed imaging changes. To ensure appropriate adjustment, image interpretation should precede any changes to treatment delivery. This study provides the methodology for image interpretation and the frequency and evolution of the changes in patients undergoing radical radiotherapy for localised and locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From December 2012 to December 2014, 250 patients with localised and locally advanced NSCLC had 2462 chest CBCT scans during the course of fractionated radical radiotherapy (RT) (3-5 daily CBCTs in the first week followed by at least weekly imaging, mean 9.5 per patient, range 1-21). All CBCT images were reviewed describing changes and their evolution using diagnostic imaging definitions and validated by an independent chest radiologist. RESULTS: During radical RT for NSCLC 328 imaging changes were identified on CBCT in 180 (72%) patients; 104 (32%) had reduction and 41 (13%) increase in tumour size; 48 (15%) had changes in consolidations contiguous to the primary lesion, 26 (8%) non-contiguous consolidations, 43 (13%) changes in tumour cavitation, 36 (11%) pleural effusion and 30 (9%) changes in atelectasis. In 105 patients imaging changes were noted in continuity with the treated tumour of which only 41 (39%) represented tumour enlargement; others included new or enlarging adjacent consolidation (34%), and new or enlarging atelectasis (19%). The changes evolved during treatment. CONCLUSION: Imaging changes on CBCT include real and apparent changes in tumour size and parenchymal changes which evolve during treatment. Correct image interpretation, particularly when occurring adjacent to the tumour, is essential prior to adjustment to treatment delivery.

Improving outcomes in non-small cell lung cancer; population analysis of radical radiotherapy.

AIM: Regional utilisation of radical radiotherapy (RT) in non-small cell lung cancer (NSCLC) was used to define optimal utilisation to improve outcome and as a surrogate for evidence of RT efficacy. PATIENTS & METHODS: 65,412 NSCLC cases diagnosed in England 2012-13 were linked to comprehensive national radiotherapy dataset, hospital admissions and the Office of National Statistics. Geographical variation in utilisation was determined using a multivariate binary logistic regression analysis after adjusting for age, stage, deprivation, comorbidity and other radical treatment and the effect of radical RT utilisation on survival was investigated. Survival was adjusted for dependent and independent variables and the effect of differing levels of utilisation was assessed by the log likelihood test. RESULTS: 17.6% cases potentially eligible for radical RT (stages 0-III) received radiotherapy with radical intent. Utilisation of radical RT had an impact on survival (p < 0.00001). Adjusting for all prognostic and treatment variables counties with lowest utilisation (≤15%) had the worst survival (HR = 1.13). The highest utilisation quintile counties (≥25%) had worse survival compared to counties with lower utilisation (≈20%) (p < 0.0001). Analysis of stages II&III showed the same pattern; increase in utilisation from 20% to ≥25% resulting in a 3% drop in 2-year population survival (p = 0.001). CONCLUSION: The utilisation of radical RT has a significant impact on NSCLC population survival. Improvement in survival of NSCLC population can be achieved by offering radical RT to a larger proportion of patients while avoiding excessive use. Geographical variation in RT utilisation provides indirect evidence of survival benefit of radical radiotherapy.

Radiotherapy for pituitary adenomas.

This article describes the technical aspects and the clinical results of conventional radiotherapy and modern stereotactic radiotherapy for pituitary adenomas. Systematic review of the published literature provides a factual basis for the comparison and the selection of appropriate radiation technique in patients who have secreting and nonfunctioning pituitary adenomas not cured with surgery and medical therapy.

EORTC 22972-26991/MRC BR10 trial: fractionated stereotactic boost following conventional radiotherapy of high grade gliomas. Clinical and quality-assurance results of the stereotactic boost arm.

BACKGROUND AND PURPOSE: The EORTC trial No. 22972 investigated the role of an additional fractionated stereotactic boost (fSRT) to conventional radiotherapy for patients with high grade gliomas. A quality-assurance (QA) programme was run in conjunction with the study and was the first within the EORTC addressing the quality of a supposedly highly accurate treatment technique such as stereotactic radiotherapy. A second aim was to investigate a possible relation between the clinical results of the stereotactic boost arm and the results of the QA. MATERIALS AND METHODS: The trial was closed in 2001 due to low accrual. In total, 25 patients were randomized: 14 into the experimental arm and 11 into the control arm. Six centres randomized patients, 8 centres had completed the dummy run (DR) for the stereotactic boost part. All participating centres (9) were asked to complete a quality-assurance questionnaire. The DR consisted of treatment planning according to the guidelines of the protocol on 3 different tumour volumes drawn on CT images of a humanized phantom. The SRT technique to be used was evaluated by the questionnaire. Clinical data from patients recruited to the boost arm from 6 participating centres were analysed. RESULTS: There was a full compliance to the protocol requirements for 5 centres. Major and minor deviations in conformality were observed for 2 and 3 centres, respectively. Of the 8 centres which completed the DR, one centre did not comply with the requirements of stereotactic radiotherapy concerning accuracy, dosimetry and planning. Median follow-up and median overall survival were 39.2 and 21.4 months, respectively. Acute and late toxicities of the stereotactic boost were low. One radiation necrosis was seen for a patient who has not received the SRT boost. Three reported serious adverse events were all seizures and probably therapy-related. CONCLUSIONS: Overall compliance was good but not ideal from the point of view of this highly precise radiation technique. Survival in the subgroup of patients with small volume disease was encouraging, but the study does not provide sufficient information about the potential value of fSRT boost in patients with malignant glioma.Toxicity due to an additional stereotactic boost of 20 Gy in 4 fractions was low and may be considered as a safe treatment option for patients with small tumours.

Defining the margins in the radical radiotherapy of non-small cell lung cancer (NSCLC) with active breathing control (ABC) and the effect on physical lung parameters.

BACKGROUND: The effectiveness of ABC has been traditionally measured as the reduction in internal margin (IM) within the planning target volume (PTV). Not to overestimate the benefit of ABC, the effect of patient movement during treatment also needs to be taken into account. We determined the IM and set-up error with ABC and the effect on physical lung parameters compared to standard margins used with free breathing. We also assessed interfraction oesophageal movement to determine a planning organ at risk volume (PRV). MATERIALS AND METHODS: Two sequential studies were performed using ABC in NSCLC patients suitable for radical radiotherapy (RT). Twelve out of 14 patients in Study 1 had tumours visible fluoroscopically and had intrafraction tumour movement assessed with and without ABC. Sixteen patients were recruited to Study 2 and had interfraction tumour movement measured using ABC in a moderate deep inspiration breath-hold, of these 7 patients also had interfraction oesophageal movement recorded. Interfraction movement was assessed by CT scan prior to and in the middle and final week of RT. Displacement of the tumour centre of mass and oesophageal borders relative to the first scan provided a measure of movement. Set-up error was measured in 9 patients treated with an in-house lung board adapted for the ABC device. Combining movement and set-up errors determined PTV and PRV margins with ABC. The effect of ABC on mean lung dose (MLD), lung V20 and V13 was calculated. RESULTS: ABC in a moderate deep inspiration breath-hold was tolerated in 25 out of 30 patients (83%) in Study 1 and 2. The random contribution of periodic tumour motion was reduced by 90% in the y direction with ABC compared to free-breathing. The magnitude of motion reduction was less in the x and z direction. Combining the systematic and random set-up error in quadrature with the systematic and random intrafraction and interfraction tumour variations with ABC results in a PTV margin of 8.3mm in the x direction, 12.0mm in the y direction and 9.8mm in the z direction. There was a relative mean reduction in MLD, lung V20 and V13 of 25%, 21% and 18% with the ABC PTV compared to a free-breathing PTV. Oesophageal movement combined with set-up error resulted in an isotropic PRV of 4.7 mm. CONCLUSIONS: The reduction in PTV size with ABC resulted in an 18-25% relative reduction in physical lung parameters. PTV margin reduction has the potential to spare normal lung and allow dose-escalation if coupled with image-guided RT. The oesophageal PRV needs to be considered when irradiating central disease and is of increasing importance with altered RT fractionation and concomitant chemoradiation schedules. Further reductions in PTV and PRV may be possible if patient set-up error was minimised, confirming that attention to patient immobilisation is as important as attempts to control tumour motion.

Hypofractionated stereotactic radiotherapy in the management of recurrent or residual medulloblastoma/PNET.

PURPOSE: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy in the management of locally recurrent or residual central nervous system (CNS) primitive neuroectodermal tumors (PNETs). PATIENTS AND METHODS: Between 1991 and 2005, 12 patients with locally recurrent medulloblastoma and two patients with residual supratentorial PNET were treated with hypofractionated stereotactic conformal radiotherapy (SCRT). Nine patients were treated for first recurrence, two patients after the 2nd, and one patient after 3rd recurrence. Median age at diagnosis was 20 years (range: 4-35 years) and median age at SCRT 25 years (range: 7-41 years). Nine of 12 patients underwent resection at recurrence and 13 patients received at least one cycle of chemotherapy prior to SCRT. All received focal SCRT (30-40 Gy/6-8 #) using non-coplanar arcs (n = 6) or fixed conformal non-coplanar fields (n = 8). RESULTS: Median overall survival was 29 months (95% CI: 6-51 months) and median progression-free survival was 12 months (95% CI: 5-19 months). Local progression-free survival at 1 and 3 years was 80% (95% CI: 55-100%) and 48% (95% CI: 11-85%). Causes of death were recurrent CNS disease (n = 7), herpes encephalitis (n = 1), and metastatic PNET outside the CNS (n = 1). CONCLUSION: Hypofractionated SCRT provides effective local control with acceptable toxicity for patients with recurrent localized PNET. However, overall long-term disease control is rare and limited by the occurrence of CSF mediated relapses, which thus could benefit from intensive systemic chemotherapy as part of the primary relapse strategy even in local recurrences. Larger multi-national studies will be necessary to assess the value of such combined treatment approaches.

Treatment of lung cancer using volumetric modulated arc therapy and image guidance: a case study.

BACKGROUND: Volumetric modulated arc therapy (VMAT) is a radiotherapy technique in which the gantry rotates while the beam is on. Gantry speed, multileaf collimator (MLC) leaf position and dose rate vary continuously during the irradiation. For optimum results, this type of treatment should be subject to image guidance. The application of VMAT and image guidance to the treatment of a lung cancer patient is described. MATERIAL AND METHODS: In-house software AutoBeam was developed to facilitate treatment planning for VMAT beams. The algorithm consisted of a fluence optimisation using the iterative least-squares technique, a segmentation and then a direct-aperture optimisation. A dose of 50 Gy in 25 fractions was planned, using a single arc with 35 control points at 10 degrees intervals. The resulting plan was transferred to a commercial treatment planning system for final calculation. The plan was verified using a 0.6 cm(3) ionisation chamber and film in a rectangular phantom. The patient was treated supine on a customised lung board and imaged daily with cone-beam CT for the first three days then weekly thereafter. RESULTS: The VMAT plan provided slightly improved coverage of the planning target volume (PTV) and slightly lower volume of lung irradiated to 20 Gy (V(20)) than a three-field conformal plan (PTV minimum dose 85.0 Gy vs. 81.8 Gy and lung V(20) 31.5% vs. 34.8%). The difference between the measured and planned dose was -1.1% (measured dose lower) and 97.6% of the film passed a gamma test of 3% and 3mm. The VMAT treatment required 90 s for delivery of a single fraction of 2 Gy instead of 180 s total treatment time for the conformal plan. CONCLUSION: VMAT provides a quality dose distribution with a short treatment time as shown in an example of a lung tumour. The technique should allow for more efficient delivery of high dose treatments, such as used for hypofractionated radiotherapy of small volume lung tumours, and the technique may also be used in conjunction with Active Breathing Control, where fewer breath holds will be required.

Combining immunotherapy and radiotherapy in lung cancer.

Immunotherapy has become standard of care in advanced non-small cell lung cancer (NSCLC) in a number of settings. Radiotherapy remains an important and potentially curative treatment for localized and locally advanced NSCLC not amenable to surgery. While the principal cytotoxic effect of ionizing radiation is via DNA damage, the effect on tumour microenvironment, promoting dendritic cell presentation of tumour-derived antigens to T cells stimulating the host adaptive immune system to mount an immune response against tumours cells, has become of particular interest when combining immunomodulating agents with radiation. The 'abscopal effect' of radiation where non-irradiated metastatic lesions may respond to radiation may be immune-mediated, via radiation primed anti-tumour T cells. Immune priming by radiation offers the potential for increasing the efficacy of immunotherapy and this is subject to on-going clinical trials underpinned by immunological bioassays. Increasing understanding of the interaction between tumour, radiation and immune cells at a molecular level provides a further opportunity for intervention to enhance the potential synergy between radiation and immunotherapy. Applying the potential efficacy of combination therapy to clinical practice requires caution particularly to ensure the safety of the two treatment modalities in early phase clinical trials, many of which are currently underway. We review the biological basis for combining radiation and immunotherapy and examine the existing pre-clinical and clinical evidence and the challenges posed by the new combination of treatments.

Comparison of inverse-planned three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for non-small-cell lung cancer.

PURPOSE: Lungs are the major dose-limiting organ during radiotherapy (RT) for non-small-cell lung cancer owing to the development of pneumonitis. This study compared intensity-modulated RT (IMRT) with three-dimensional conformal RT (3D-CRT) in reducing the dose to the lungs. METHODS: Ten patients with localized non-small-cell lung cancer underwent computed tomography (CT). The planning target volume (PTV) was defined and the organs at risk were outlined. An inverse-planning program, AutoPlan, was used to design the beam angle-optimized six-field noncoplanar 3D-CRT plans. Each 3D-CRT plan was compared with a series of five IMRT plans per patient. The IMRT plans were created using a commercial algorithm and consisted of a series of three, five, seven, and nine equidistant coplanar field arrangements and one six-field noncoplanar plan. The planning objectives were to minimize the lung dose while maintaining the dose to the PTV. The percentage of lung volume receiving >20 Gy (V20) and the percentage of the PTV covered by the 90% isodose (PTV90) were the primary endpoints. The PTV90/V20 ratio was used as the parameter accounting for both the reduction in lung volume treated and the PTV coverage. RESULTS: All IMRT plans, except for the three-field coplanar plans, improved the PTV90/V20 ratio significantly compared with the optimized 3D-CRT plan. Nine coplanar IMRT beams were significantly better than five or seven coplanar IMRT beams, with an improved PTV90/V20 ratio. CONCLUSION: The results of our study have shown that IMRT can reduce the dose to the lungs compared with 3D-CRT by improving the conformity of the plan.