Radiation Fractionation Schedules Research Articles

Impact of Performance Status and Comorbidity on Palliative Radiation Treatment Tolerance and End-Of-Life Decision-Making

PurposePrevious studies have indicated a relationship between functional status and comorbidity on overall survival when treating patients with bone and brain metastases. However, the degree to which these findings have been integrated into modern-day practice remains unknown. This study examines the impact of performance measures, including Karnofsky Performance Status (KPS) and comorbidity, on palliative radiation therapy treatment tolerance and fractionation schedule. The relationship between a shorter fractionation schedule (SFx) and pending mortality is examined. Methods and materialsThis study included patients who were treated with palliative intent to the brain or bone between January 1, 2016 and June 30, 2016. Demographic and medical characteristics collected included KPS score (stratified as good [90-100], fair [70-80], and poor (≤60]), socioeconomic status, comorbidity (binary measure using the Adult Comorbidity Evaluation-27 scale), site of metastatic disease, and treatment facility. Univariable analyses were performed using the Cox proportional hazards regression model to assess the impact of the variables on the prescribed number of fractions (binary measure, ≥10 [long fractionation schedule], and <10 [SFx]), and major treatment interruptions (MTIs; defined as missing ≥3 radiation therapy treatment days or ending treatment prematurely). ResultsA total of 145 patients were eligible for study inclusion, including 95 patients who were treated for bony metastatic disease and 50 patients for brain metastases. High comorbidity (P = .029) and both fair (P = .051) and poor (P = .065) functional status were associated with more frequent MTIs. However, high comorbidity and low KPS score were not associated with shorter treatment plans. In addition, patients with an earlier time to death were not more likely to receive an SFx (P = .871). ConclusionsLow KPS and elevated comorbidity scores predict for a poorer prognosis and more frequent MTIs; however, there was no indication that physicians incorporated this information in the fractionation scheduling.

The influence of fractionated radiotherapy on the stability of spinal bone metastases: a retrospective analysis from 1047 cases

BackgroundThe effect of radiotherapy, in particular the application of different multi-fraction schedules in the management of unstable spinal bone metastases (SBM), is incompletely understood. This study aims to compare the radiological response regarding various dose and fractionation schedules of radiotherapy in the palliative treatment of SBM.MethodsWe retrospectively assessed 1047 patients with osteolytic SBM, treated with palliative radiotherapy at our department between 2000 and 2015. Lung cancer (40.2%), breast (16.7%) and renal cancer (15.2%) were the most common solid tumors in this study. Different common multi-fraction regimen (5x4Gy, 10x3Gy, 14 × 2.5Gy and 20x2Gy) were compared with regard to radiological response and recalcification at 3 and 6 months after radiotherapy. The Taneichi score was used for classification of osteolytic SBM.ResultsMedian follow up was 6.3 months. The median overall survival (OS) in the short-course radiotherapy (SCR) group using less than 10 treatment fractions was 5.5 months vs. 9.5 months in the long-course radiotherapy (LCR) group using in excess of 10 fractions (log rank p < .0001). Overall survival (OS) in the SCR group after 3 and 6 months was 66.8 and 49.1%, respectively vs 80.9 and 61.5%, respectively in the LCR group.17.6% (n = 54/306) and 31.1% (n = 89/286) of unstable SBM were classified as stable in the SCR group at 3 and 6 months post radiotherapy, respectively (p < .001 for both). In the LCR group, 24.1% (n = 28/116) and 34.2% (n = 38/111) of unstable SBM were stabilized after 3 and 6 months, respectively (p < .001 for both).ConclusionsOur study shows no significant difference in stabilization achieving recalcification rates between multi-fraction schedules (SCR vs. LCR) in the palliative management of unstable SBM. Both groups with multi-fraction regimen demonstrate a stabilizing effect following 3 and 6 months after radiotherapy.

Different fractionation schedules of radiotherapy in preoperative concurrent chemoradiotherapy for thoracic esophageal cancer: a clinical study

Objective To investigate the clinical efficacy and safety of preoperative hypofractionated and conventionally-fractionated chemoradiotherapy for thoracic esophageal cancer. Methods A total of 86 patients with thoracic esophageal cancer receiving chemoradiotherpy in Sichuan Cancer Hospital between 2002 and 2011 were enrolled and randomized into the preoperative hypofractionated chemoradiotherapy group (group A, n=41, 30 Gy in 10 fractions for 2 weeks) and conventionally-fractionated chemoradiotherapy group (group B, n=45, 40 Gy in 20 fractions for 4 weeks). Surgery was performed at 2-6 weeks after chemoradiotherapy. The probability of patients’ survival was estimated by Kaplan-Meier method and analyzed by log-rank test. Results In groups A and B, the pathological downstaging rates were 68% and 56%(P=0.270), the R0 resection rates were 95% and 89%(P=0.437) and the pCR rates of 32% and 24%(P=0.480). The 1-, 3-and 5-year overall survival (OS) rates were 78% and 69%, 44% and 44%, 29% and 33%(P=0.114, 0.223, 0.289), and the progression-free survival (PFS) rates were 71% and 62%, 39% and 38%, 24% and 29%(P=0.211, 0.689, 0.331), respectively. The incidence rate of chemoradiothery-and surgery-related adverse events did not differ between two groups (P=0.089-0.872). The average length of hospital stay, radiotherapy cost and preoperative treatment costs in group A were significantly less compared with those in group B (P=0.000, 0.000, 0.000). Conclusions Both preoperative hypofractionated and conventionally-fractionated chemoradiotherapy can be used as the regimen of preoperative chemoradiotherapy in patients with resectable thoracic esophageal carcinoma. Compared with conventionally-fractionated chemoradiotherapy, preoperative hypofractionated chemoradiotherapy has shorter treatment cycle, shorter length of hospital stay and lower radiotherapy cost, which is more easily accepted by patients. Key words: Esophageal neoplasm/preoperative chemoradiotherapy; Hypofractionated; Conventional fractionated; Prognosis

Matrix metalloproteinase expression is altered in the small and large intestine following fractionated radiation in vivo.

Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. Dark Agouti rats were treated with fractionated radiation (3 × 2.5Gy/week for 6weeks). Rats were killed at 3, 6 and 15weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p= 0.0359) and the colon (p= 0.0134) 6weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.

Comparison of Locoregional Control, Acute Radiation Toxicities and Patient Compliance between Two Different Radiation Fractionation Schedules with Concurrent Chemotherapy in Oropharyngeal Cancer

Comparison of Locoregional Control, Acute Radiation Toxicities and Patient Compliance between Two Different Radiation Fractionation Schedules with Concurrent Chemotherapy in Oropharyngeal Cancer

The Evolution of Tumour Composition During Fractionated Radiotherapy: Implications for Outcome

Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially resolved mathematical model of tumour growth, first proposed by Greenspan (Stud Appl Math 51:317–340, 1972), to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intratumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon regrowth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.

Assessment of Ki67 in relation to radiotherapy (RT) fractionation and prognosis in the CHHiP (CRUK/06/016) trial.

98 Background: A uniform fractionation schedule is used to deliver external beam RT for localised prostate tumours Individualising fractionation according to tumour biology may improve outcomes. In addition recurrence rates after RT vary considerably and better prognostic markers are needed to guide treatment choices. This study aims to identify if the cell proliferation marker Ki67 predicts response to RT fractionation in CHHiP, a randomised trial of 3 RT fractionation schedules. It also aims to identify if Ki67 predicts prognosis. Methods: A matched case:control study design was used, patients with biochemical or clinical failure &gt; 2 years after RT (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, PSA, Tumour-stage) and fractionation schedule. Immunohistochemical (IHC) staining of diagnostic biopsy sections was carried out using the MIB1 Ki67 antibody. Two independent investigators scored Ki67 using the unweighted global method (1) to derive a mean and maximum percentage of cells staining positive (mean Ki67 and maximum Ki67 respectively). Conditional logistic regression models were fitted with interaction terms between the biomarker and the fractionation schedules to determine whether Ki67 predicted BCR according to fractionation. Secondly models were fitted using the entire case:control study sample to estimate the prognostic value of Ki67 on risk of BCR. Results: Ki67 results were available for 173 matched pairs. The interaction terms between Ki67 and the fractionation schedules were not significant. However mean and maximum Ki67 were significant prognostic markers for BCR in a model adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR is estimated to increase by 9% per 1 point increase in mean Ki67 (OR = 1.09, 95%CI:1.04–1.15, p = 0.001). Conclusions: Ki67 did not predict BCR according to fractionation schedule in CHHiP, however it did predict prognosis independently of established prognostic factors. Additional IHC biomarkers are under evaluation.

Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval &gt;0.5 were considered statistically significant. Any constraint derived in &lt;99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]

Methodology for tissue sample collection within a translational sub-study of the CHHiP trial (CRUK/06/016), a large randomised phase III trial in localised prostate cancer

BackgroundThis article presents the methodology for tissue sample collection in Trans-CHHiP, the main translational study within the CHHiP (Conventional or Hypofractionated High dose intensity modulated radiotherapy in Prostate cancer, ISRCTN 97182923) trial. The CHHiP trial randomised 3216 men with localised prostate cancer to 3 different radiotherapy fractionation schedules. Trans-CHHiP aims to identify biomarkers of fraction sensitivity. MethodsWe outline the process of tissue collection, including central review by a study-specific specialist uropathologist and comparison of the centrally-assigned Gleason grade group with that assigned by the recruiting-centre pathologist. Results2047 patients provided tissue from 107 pathology departments between August 2012 and April 2014. A highly motivated Clinical Trials Unit chasing samples and a central Trans-CHHiP group that regularly reviewed progress were important for successful sample collection. Agreement in Gleason grade group assigned by the recruiting centre pathologist and the central study-specific uropathologist occurred in 886 out of 1854 (47.8%) cases. Key lessons learned were the need for prospective consent for tissue collection when recruiting patients to the main trial, and the importance of Material Transfer Agreement (MTA) integration into the initial trial site agreement. ConclusionsThis methodology enabled collection of 2047 patient samples from a large randomised radiotherapy trial. Central pathological review is important to minimise subjectivity in Gleason grade grouping and the impact of grade shift.

Ki67 Is an Independent Predictor of Recurrence in the Largest Randomized Trial of 3 Radiation Fractionation Schedules in Localized Prostate Cancer

PurposeTo assess whether the cellular proliferation marker Ki67 provides prognostic information and predicts response to radiation therapy fractionation in patients with localized prostate tumors participating in a randomized trial of 3 radiation therapy fractionation schedules (74 Gy/37 fractions vs 60 Gy/20 fractions vs 57 Gy/19 fractions).Methods and MaterialsA matched case–control study design was used; patients with biochemical/clinical failure >2 years after radiation therapy (BCR) were matched 1:1 to patients without recurrence using established prognostic factors (Gleason score, prostate-specific antigen, tumor stage) and fractionation schedule. Immunohistochemistry was used to stain diagnostic biopsy specimens for Ki67, which were scored using the unweighted global method. Conditional logistic regression models estimated the prognostic value of mean and maximum Ki67 scores on BCR risk. Biomarker–fractionation interaction terms determined whether Ki67 was predictive of BCR by fractionation.ResultsUsing 173 matched pairs, the median for mean and maximum Ki67 scores were 6.6% (interquartile range, 3.9%-9.8%) and 11.0% (interquartile range, 7.0%-15.0%) respectively. Both scores were significant predictors of BCR in models adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR were estimated to increase by 9% per 1% increase in mean Ki67 score (odds ratio 1.09; 95% confidence interval 1.04-1.15, P = .001). Interaction terms between Ki67 and fractionation schedules were not statistically significant.ConclusionsDiagnostic Ki67 did not predict BCR according to fractionation schedule in CHHiP; however, it was a strong independent prognostic factor for BCR.

Myositis following spine radiosurgery for metastatic disease: a case series.

OBJECTIVE Spinal stereotactic body radiation therapy (SBRT) has emerged as an attractive method to deliver high doses of radiation to oligometastatic spinal tumors with radioresistant histology. Because SBRT is a palliative therapy, attention to potential radiation toxicities is paramount when counseling patients. The objective of this study was to report radiation-induced myositis after SBRT, a previously undescribed complication. METHODS A total of 667 patients received 891 spine SBRT treatments (either 24 Gy in 1 fraction or 27 Gy in 3 fractions) from 2011 to 2016 and underwent retrospective review. Eleven patients were identified as having radiographic evidence of myositis following SBRT. Clinical and pathologic results were collected, including receipt of anti-vascular endothelial growth factor (VEGF) therapy, radiation dose, equivalent dose in 2-Gy fractions (EQD2), biologically effective dose (BED), and volume of muscle treated. Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.03). Univariate statistical analyses were performed to evaluate the relationships between radiation fractionation schedule and myositis and between anti-VEGF therapy and myositis. RESULTS The cumulative incidence of myositis was 1.9% at 1 year. The median of the mean dose administered to muscle with myositis was 17.5 Gy. The median EQD2 was 55.1 Gy, and the median BED was 82.7 Gy. The median time to the development of clinical symptoms was 1.4 months, while the median time to imaging evidence was 4.7 months. Two patients (18.2%) had CTCAE grade 3 complications. Single-fraction spine SBRT (HR 4.5, 95% CI 1.2-16.9; p = 0.027) was associated with increased risk of developing myositis whereas receipt of anti-VEGF therapy was not (HR 2.2, 95% CI 0.6-7.1; p = 0.2). CONCLUSIONS Radiation myositis following spinal radiosurgery is a rare but important complication. Single-fraction treatment schedules may be associated with increased risk of myositis but should be validated in a larger series.

Comparison of Single Versus Multifraction Radiotherapy in Palliation of Painful Bone Metastases.

BackgroundBone is a common site of dissemination in advanced cancer accounting for one-third of all distant metastases. Various fractionation schedules of radiotherapy have been used for palliation of bone metastases. The aim of this study was to compare three schedules of external radiation therapy (8 Gy single session versus 20 Gy/5 fractions versus 30 Gy/10 fractions) for palliative management of bone metastases.MethodsIn the present study, 60 patients of bone metastases from any primary site were enrolled and randomly divided into three groups of 20 patients each by draw of lots. These patients received palliative external beam radiation therapy to the involved site. Patients were given 8 Gy single session, 20 Gy/5 fractions/1 week and 30 Gy/10 fractions/2 weeks in groups I, II and III, respectively.ResultsThe percentage of patients with overall pain relief was 80% in group I, 75% in group II and 85% in group III (P = 0.7). The number of patients with complete pain relief was 4 (20%) in each group. Maximum patients got pain relief at 4 weeks post-radiotherapy. The number of patients with improved performance status was 4 (20%) in group II and 2 (10%) each in groups I and III (P = 0.5). Thirteen (65%) patients in each of the groups had decreased analgesic requirement at 2-month follow-up. Retreatment rate was more in the single fraction (20%) compared to only 5% in group II and none in the group III (P = 0.05).ConclusionFrom the present study we conclude that 8 Gy single fraction is as effective as multifraction radiotherapy for the palliation of painful bone metastases. However, for a center like ours being the only Government Tertiary Cancer Care Centre in the State, general consensus drawn after this study, recommends external radiation therapy 20 Gy/5 fraction regimen to be an appropriate means of palliation of painful bone metastases.

Optimization of radiotherapy fractionation schedules based on radiobiological functions.

To present a method for optimizing radiotherapy fractionation schedules using radiobiological tools and taking into account the patient´s dose-volume histograms (DVH). This method uses a figure of merit based on the uncomplicated tumour control probability (P+) and the generalized equivalent uniform dose (gEUD). A set of doses per fraction is selected in order to find the dose per fraction and the total dose, thus maximizing the figure of merit and leading to a biologically effective dose that is similar to the prescribed schedule. As a clinical example, a fractionation schedule for a prostate treatment plan is optimized and presented herein. From a prescription schedule of 70 Gy/35 × 2 Gy, the resulting optimal schema, using a figure of merit which only takes into account P+, is 54.4 Gy/16 × 3.4 Gy. If the gEUD is included in that figure of merit, the result is 65 Gy/26 × 2.5 Gy. Alternative schedules, which include tumour control probability (TCP) and the normal tissue complication probability (NTCP) values are likewise shown. This allows us to compare different schedules instead of solely finding the optimal value, as other possible clinical factors must be taken into account to make the best decision for treatment. The treatment schedule can be optimized for each patient through radiobiological analysis. The optimization process shown below offers physicians alternative schedules that meet the objectives of the prescribed radiotherapy. Advances in knowledge: This article provides a simple, radiobiological-function-based method to take advantage of a patient's dose-volume histograms in order to better select the most suitable treatment schedule.

Considerations for the Use of Dorsal Column Stimulation for Lumbosacral Radiation Neuritis of the Nerve Root in the Spine Tumor Patient (A Case Series)

Background: Radiation therapy (RT) has become a mainstay in the treatment of various malignancies. Unfortunately, a potential side effect of this modality is radiation-induced neuritis. The time-course is varied and the emergence of pain syndromes can be delayed by several years after the completion of treatment. Risk factors include the total radiation dose, fractionation schedule, and radiation field size. Spinal cord stimulation (SCS) may have an important role in attenuating the symptoms of radiation-induced neuritis. Objectives: We aim to characterize a case series of oncologic patients who underwent SCS to treat iatrogenic radiation neuritis of the lumbosacral nerve roots. Study Design: This is a retrospective review of 4 cases of patients who were eligible for either intrathecal drug delivery or SCS (magnetic resonance imaging [MRI] conditional devices for spine surveillance), of which each patient elected to have a SCS trial and possible permanent implantation. Setting: The data were collected at a major cancer center in the US. Methods: In this case series, we present 4 patients with radiation-induced neuropathy. For each patient, we describe the use of SCS, which uses electric impulse generation, in an effort to treat the patient’s symptoms. To assess for efficacy, we compare pre- and post-procedure numerical rating scale (NRS) pain scores and post-procedure pain medication requirements. Results: Each patient had marked improvement in their pain (&gt; 50%) during the trial lead placement and proceeded to the permanent implant. In subsequent months and years, the patients decreased their opioid utilization and reported an improvement in their overall pain. Limitations: This case series is a small sample size of heterogeneous malignancies with radiation treatment to the spine. Conclusions: Radiation-induced neuritis remains a severe and limiting outcome that some patients must live with after RT. Survivors of malignancy have often found this pathology to severely impact their quality of life, and it is difficult to treat. We have described the utilization of spinal cord neuromodulation as an effective treatment modality in the spine tumor patient population. Further research is needed to maximize the benefit and ensure appropriate case selection in the future. Key words: Radiation neuritis, radiation neuropathy, oncologic lumbar radiculopathy, spinal cord stimulation, neuromodulation, dorsal column stimulation, spinal tumor pain, MRI conditional spinal cord stimulation

Once Versus Twice Daily Fractionation for Limited Stage SCLC

Despite phase III data indicating improved survival with twice daily fractionation for limited stage small cell lung cancer (SCLC), logistics of twice daily treatment and potential for increased toxicity have limited its utilization. We sought to compare overall and lung cancer specific survival between once daily and twice daily fractionation for limited stage SCLC. Using the VA Central Cancer Registry (VACCR), limited stage SCLC patients diagnosed from 1/2001-12/2010 were identified. Data regarding fractionation, co-morbidities, and treatment toxicity were obtained from the VA Corporate Data Warehouse (VACDW). Cause of death was obtained from the National Death Index. Radiation fractionation was determined by CPT codes for treatment limited to within 180 days of diagnosis or by review of VACDW abstracted data. Charlson Comorbidity Index (CCI) was calculated using ICD-10 codes in the year before diagnosis. Treatment toxicity was determined based on ICD-10 codes up to 180 days after treatment. 3,512 patients were identified with limited stage SCLC; radiation fractionation was able to be determined for 942 patients. 822 patients had once daily fractionation and 120 had twice daily fractionation. Median follow-up was 78 months. Mean age was 64.6 years, 97.9% were male and 84.8% were white. 96.0% were current/former smokers. 73.1% had stage III disease. Overall survival (HR 1.19, 95% CI 0.96-1.47, p=0.12) and lung cancer specific survival (HR 1.11, 95% CI 0.87-1.40, p=0.39) were similar between the two fractionation schedules. Overall survival of propensity score matched cohorts was also similar between daily and twice daily treatment (HR 0.87, 95% CI 0.65-1.16, p=0.33). There were higher rates of mucositis/esophagitis (27.5% vs 14.6%), nausea (28.3% vs 11.4%), and acute kidney injury (40.0% vs 25.7%, p<0.05 for all) with twice daily fractionation. In this VA population of limited stage SCLC patients diagnosed from 2001-2010, there was no difference in overall survival or lung cancer specific survival with twice daily versus daily radiation fractionation schedules, although toxicity was worse with twice daily treatment. These data agree with a preliminary report of an ongoing phase III study and suggest no benefit to a twice daily fractionation schedule for limited stage SCLC.

Consideration of patient and disease characteristics in selecting radiation regimens for treatment of bone metastases

PurposeRadiation therapy is one of the mainstays of treatment for painful bone metastases; however, the optimal fractionation and dosing of radiation for a given patient and disease characteristics are still subject to debate. Methods and materialsWe retrospectively examined 475 patients who received radiation for bone metastases at our institution from 2009 through 2014 and evaluated survival outcomes based on parameters of their first treatment course and patient demographics. Kaplan-Meier analysis was used to analyze factors associated with overall survival (OS). A recursive partition analysis (RPA) was used to generate a decision tree of patient characteristics resulting in significant differences in survival. A Cox model was used to verify the RPA and evaluate the significance of biologically equivalent dose (BED) along with other factors. ResultsIn our cohort, median age was 62 years and median Karnofsky performance status (KPS) was 70. Survival time by primary tumor type: breast (median, 35.9 months), prostate (12.8 months), other (median, 11.0 months), lung (median, 5.3 months), and gastrointestinal (median, 4.0 months) (P < .0001). Primary tumor type and KPS significantly affected survival, whereas age was also significant for survival in certain primary tumor types. Pain control was not found to be significantly affected by primary tumor type (P = .72) or BED (P = .14). ConclusionOur data demonstrate that selection of radiation fractionation schedules should take into account primary tumor type, KPS, and age, and we have generated an RPA model including these factors to help guide decision making. We also found that shorter fractionation schedules are as effective as longer fractionation schedules for pain control, regardless of primary tumor type.

(P089) Comparison of Survival by Different Palliative Radiation Therapy Fractionation Schedules

Choice of palliative radiotherapy regimen has taken on greater importance in recent years with the 2013 ASTRO Choosing Wisely campaign recommending against protracted fractionation schemes for palliation of bone metastases and encouraging single-fraction treatment for appropriately selected patients. The aims of this project were to 1) determine survival based upon palliative fractionation scheme utilized and 2) determine additional factors which predict survival. We identified a cohort of 1292 patients (569 female, 723 male) treated with palliative intent from 2000-2014 who were treated according to one of four palliative treatment schedules: 37.5 Gy in 15 fractions (n= 318), 30 Gy in 10 fractions (n = 982), 20 Gy in 5 fractions (n = 262), 8 Gy in a single fraction (n = 139). Death dates were obtained from medical records, Social Security Death Index, and publicly-available obituaries. Performance status, marital status, burden of metastatic disease and insurance type were also noted. SAS was used to generate a multivariate model with time from treatment to death as a continuous dependent variable. We found that the length of treatment correlated directly with survival, with the exception of no significant difference between single-fraction and 5-fraction palliative regimens. Median survival was 13.4, 9.8, 7.0 and 6.9 months for 15, 10, 5 and single fraction treatments, respectively. Performance status and insurance status were also correlated with survival, with worse performance status and lack of insurance correlating with decreased survival. Given that patients receiving shorter courses of palliative radiotherapy have a shorter survival, this indicates we may be appropriately selecting shorter treatment for patients with limited survival. However, the lack of survival difference between patients treated with single-fraction and 5-fraction palliative regimens supports consideration of single-fraction treatment over 5-fraction treatment.

Optimal Radiation Therapy for Small Cell Lung Cancer.

Radiation therapy plays an important role in the management of both limited stage and extensive stage small cell lung cancer. For limited stage disease, there has been a trend toward reduced size of thoracic radiation fields, which has the potential to reduce toxicity. FDG-PET staging helps make this possible by more accurately identifying areas of nodal and metastatic involvement. Trials have demonstrated similar outcomes using a range of radiation fractionation schedules, allowing flexibility in individualizing treatment. Using advanced radiation therapy techniques such as intensity-modulated radiation therapy, it may be possible to deliver fewer, higher dose fractions and achieve similar results to the hyperfractionated regimen. For extensive stage disease, consolidative thoracic radiation therapy after chemotherapy was recently shown to improve overall survival in certain patient subsets. Prophylactic cranial irradiation continues to play an important role in management of all stages of small cell lung cancer. Debate continues about the neurocognitive effects of this treatment, and whether MRI surveillance is an acceptable alternative. Strategies such as hippocampal avoidance may reduce the cognitive effects of prophylactic cranial irradiation in the future. Finally, in the last few years stereotactic ablative radiation therapy followed by chemotherapy has emerged as a promising treatment for stage I small cell lung cancer. This radiation treatment is usually given over 1-5 fractions and appears to provide a good rate of local control with a low rate of serious toxicity.

Fractionated abdominal irradiation induces intestinal microvascular changes in an in vivo model of radiotherapy-induced gut toxicity.

Radiotherapy-induced gut toxicity (RIGT) is associated with diarrhoea, pain and rectal bleeding and can occur as an acute or chronic toxicity. The microvasculature has been shown to be altered in the development of RIGT; however, the features are not yet characterized. We hypothesized that apoptosis of microvascular cells would occur early in the gastrointestinal tract following fractionated irradiation, followed by late microvascular changes, including sclerosis and telangiectasis. Female Dark Agouti rats were treated with a 6-week fractionated radiation schedule of 3×2.5Gy doses per week localized to the abdomen. At 3, 6 and 15weeks, the intestines were assessed for markers of acute and chronic injury including morphological changes, collagen deposition, apoptosis and proliferation. Apoptosis of microvascular cells significantly increased at 6 and 15weeks in the jejunum (p=0.0026 and p=0.0062, respectively) and at 6 and 15weeks in the colon (p<0.0001 and p=0.0005, respectively) in rats receiving fractionated radiation to the abdomen. Histopathological changes of the colon microvasculature were also seen from week 3, including thickening of the lamina propria and dilated, thickened, telangiectatic vessels. Findings of this study provide evidence of regional and timing-specific changes in the intestinal microvasculature in response to fractionated radiotherapy which may play a role in development of both acute and chronic RIGT.

Therapeutic management options for stage III non-small cell lung cancer.

Lung cancer is the leading cause of cancer death worldwide. Majority of newly diagnosed lung cancers are non-small cell lung cancer (NSCLC), of which up to half are considered locally advanced at the time of diagnosis. Patients with locally advanced stage III NSCLC consists of a heterogeneous population, making management for these patients complex. Surgery has long been the preferred local treatment for patients with resectable disease. For select patients, multi-modality therapy involving systemic and radiation therapies in addition to surgery improves treatment outcomes compared to surgery alone. For patients with unresectable disease, concurrent chemoradiation is the preferred treatment. More recently, research into different chemotherapy agents, targeted therapies, radiation fractionation schedules, intensity-modulated radiotherapy, and proton therapy have shown promise to improve treatment outcomes and quality of life. The array of treatment approaches for locally advanced NSCLC is large and constantly evolving. An updated review of past and current literature for the roles of surgery, chemotherapeutic agents, radiation therapy, and targeted therapy for stage III NSCLC patients are presented.