Radiation Fractionation Schedules Research Articles

Optimizing Radiotherapy with Immunotherapeutic Approaches.

Several factors must be considered to successfully integrate immunotherapy with radiation into clinical practice. One such factor is that concepts arising from preclinical work must be tested in combination with radiation in preclinical models to better understand how combination therapy will work in patients; examples include checkpoint inhibitors, tumor growth factor-beta (TGF-β) inhibitors, and natural killer (NK) cell therapy. Also, many radiation fields and fractionation schedules typically used in radiation therapy had been standardized before the introduction of advanced techniques for radiation planning and delivery that account for changes in tumor size, location, and motion during treatment, as well as uncertainties introduced by variations in patient setup between treatment fractions. As a result, radiation therapy may involve the use of large treatment volumes, often encompassing nodal regions that may not be irradiated with more conformal techniques. Traditional forms of radiation in particular pose challenges for combination trials with immunotherapy. This chapter explores these issues in more detail and provides insights as to how radiation therapy can be optimized to combine with immunotherapy.

Estimation of linear quadratic (LQ) model parameter alpha/beta (α/β) and biologically effective dose (BED) for acute normal tissue reactions in head and neck malignancies

Purpose: Linear-Quadratic (LQ) model has been widely used for describing radiobiological effectiveness of various fractionation schedules on tumour as well as normal tissues. This study estimates α/β for acute normal tissue reactions using Fe-plot method. Methods: 50 cases of locally advanced head and neck squamous cell carcinoma (stage III and IV) treated with external beam radiotherapy were included in this study. Patients were randomly distributed into Hyper-fractionation (HF) arm (1.2 Gy/fraction, twice daily, 6 hours apart) and conventional fractionation (CF) arm (2 Gy/fraction, once daily) with 25 cases in each arm. α/β and BED were calculated for acute normal tissue reactions using Fe-plot method. Results: In our study, the estimated values of α/β for RTOG (Radiation Therapy Oncology Group) grade 1, 2 and 3 skin reactions were 11.2 Gy, 10.1 Gy and 9 Gy respectively. Estimated values of α/β for RTOG grade 1, 2 and 3 mucosal reactions were 9.7 Gy, 8.0 Gy and 9.1 Gy respectively. For Hyper-fractionation arm, calculated BED values for grade 1, 2 and 3 skin reactions were 54.45 Gy 11.239 , 66.90 Gy 10.114 and 73.43Gy 9.001 respectively and for grade 1, 2 and 3 mucosal reactions were 33.5 Gy 9.797 , 57.8 Gy 8.011 and 70.8 Gy 9.106 respectively. For conventional fractionation arm, calculated BED values for grade 1, 2 and 3 skin reactions were 54.09 Gy 11.239 , 66.88 Gy 10.114 and 73.33 Gy 9.001 respectively and for grade 1, 2 and 3 mucosal reactions were 33.52 Gy 9.797 , 57.68 Gy 8.011 and 70.73 Gy 9.106 respectively. Conclusion: LQ model and the concept of BED provide an excellent tool to compare different fractionation schedules in radiotherapy. The estimated values of α/β for acute reacting normal tissues are in good agreement with the available literature.

Comparison of Survival by Different Palliative Radiation Therapy Fractionation Schedules

Comparison of Survival by Different Palliative Radiation Therapy Fractionation Schedules

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.

BackgroundPembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient’s own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20–40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab.Case presentationThe patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure.ConclusionsBiomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy.Trial registrationAn Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771.

Preoperative chemoradiation for locally advanced rectal cancer: comparison of three radiation dose and fractionation schedules.

Purpose:The standard radiation dose for patients with locally rectal cancer treated with preoperative chemoradiotherapy is 45–50 Gy in 25–28 fractions. We aimed to assess whether a difference exists within this dose fractionation range.Materials and Methods:A retrospective analysis was performed to compare three dose fractionation schedules. Patients received 50 Gy in 25 fractions (group A), 50.4 Gy in 28 fractions (group B), or 45 Gy in 25 fractions (group C) to the whole pelvis, as well as concurrent 5-fluorouracil. Radical resection was scheduled for 8 weeks after concurrent chemoradiotherapy.Results:Between September 2010 and August 2013, 175 patients were treated with preoperative chemoradiotherapy at our institution. Among those patients, 154 were eligible for analysis (55, 50, and 49 patients in groups A, B, and C, respectively). After the median follow-up period of 29 months (range, 5 to 48 months), no differences were found between the 3 groups regarding pathologic complete remission rate, tumor regression grade, treatment-related toxicity, 2-year locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, or overall survival. The circumferential resection margin width was a prognostic factor for 2-year locoregional recurrence-free survival, whereas ypN category was associated with distant metastasis-free survival, disease-free survival, and overall survival. High tumor regression grading score was correlated with 2-year distant metastasis-free survival and disease-free survival in univariate analysis.Conclusion:Three different radiation dose fractionation schedules, within the dose range recommended by the National Comprehensive Cancer Network, had no impact on pathologic tumor regression and early clinical outcome for locally advanced rectal cancer.

A randomized trial of a shorter radiation fractionation schedule for the treatment of localized prostate cancer.

5003Background: Men with localized prostate cancer (PC) are often treated with high dose radiotherapy (RT) over 8-9 weeks. The α-β ratio which describes the dose-response of tumors and normal tissu...

Efficacy and mucosal toxicity of concomitant chemo-radiotherapy in patients with locally-advanced squamous cell carcinoma of the head-and-neck in the light of a novel mathematical model.

In the last several decades, combined radiotherapy (RT) and chemotherapy (CT) have been recognized as feasible in locally-advanced-squamous-cell-carcinoma of the head-and-neck (LA-HNSCC). Several meta-analyses identified concurrent RT+CT (CRT) most likely effective approach respect to RT-alone. However, radiobiological models comparing different chemotherapeutic schedules against delivered RT fractionation schedule for overall survival and toxicity are still needed. Based on 9 randomized trials (2785 patients), radiobiological models and multivariate logistic regression model were used to derive dose-response curves and estimate the 5-year-overall survival (OS) and ≥G3 acute mucositis rate of CRT or RT-alone. Equivalent dose at 2 Gy/fraction (EQD2) was calculated using the linear quadratic model. The effect of CRT schedules, considering the CT type and its administration schedule and the HPV status of tumors were estimated using the univariate/multivariate logistic regression. The multivariate logistic regression model for 5y-OS indicated EQD2 and the type of CT, the chemo-sensitization fraction and the HPV status significant prognostic factors, while for toxicity both EQD2 and the concomitant administration of 5-fluorouracil (5Fu) resulted as significant prognostic factors. Combined schedules cisplatin (DDP)+/-5Fu+RT produced the higher OS compared with combined carboplatin+/-5Fu+RT or RT-alone. The concomitant administration of Fu and schedule with high EQD2 increase the rate of observed ≥G3 acute mucositis. Multivariate logistic regression models can be used to predict CRT effect in terms of OS and ≥G3-mucositis, contributing to the identification of novel treatment schedules.

Ofractionation versus conventional radiotherapy with concurrent Gemcitabine in bladder preservation of patient with bladder carcinoma

Background: This prospective, phase III study aimed at evaluation the efficacy and toxicity of hypofractionated radiation schedule versus conventional radiation given concurrent with weekly Gemcitabine. Patient and methods: Fifty one patients with transitional cell carcinoma, stage T1-4a, N0, M0 after transurethral resection [TUR] and magnetic resonance imaging, were recruited. Patients were categorized into two groups: 33 patients [in Group A] who were treated with hypofractionated radiotherapy [RT] schedule that delivered 52.5 Gy in 20 fractions and 18 patients [in Group B] who were treated with conventional RT schedule 64 Gy in 32 fractions. Both groups received weekly Gemcitabine 100mg/m². Results: the majority of patients achieved complete response (CR); in group A (81.8%) and in group B (66.7%). There were significant difference between the two study groups regarding 2 year overall survival [OS] rate (88.2% vs 75.6% in group A& B respectively, P= 0.049) and relapse free survival [RFS] (66.6% vs 56.7% in group A& B respectively with P =0.033) in favor of group A. There were significant difference between the two study groups, in favor of group A, regarding cystitis (P= 0.038) and enteritis (P ˂0.001). Conclusion: The hypofractionated radiation proved to be of higher CR rate and survival rate with the favorable toxicity profile than that of conventionally fractionated radiation schedule given concurrently with Gemcitabine.

Therapeutic interactions of autophagy with radiation and temozolomide in glioblastoma: evidence and issues to resolve.

Glioblastoma is a unique model of non-metastasising disease that kills the vast majority of patients through local growth, despite surgery and local irradiation. Glioblastoma cells are resistant to apoptotic stimuli, and their death occurs through autophagy. This review aims to critically present our knowledge regarding the autophagic response of glioblastoma cells to radiation and temozolomide (TMZ) and to delineate eventual research directions to follow, in the quest of improving the curability of this incurable, as yet, disease. Radiation and TMZ interfere with the autophagic machinery, but whether cell response is driven to autophagy flux acceleration or blockage is disputable and may depend on both cell individuality and radiotherapy fractionation or TMZ schedules. Potent agents that block autophagy at an early phase of initiation or at a late phase of autolysosomal fusion are available aside to agents that induce functional autophagy, or even demethylating agents that may unblock the function of autophagy-initiating genes in a subset of tumours. All these create a maze, which if properly investigated can open new insights for the application of novel radio- and chemosensitising policies, exploiting the autophagic pathways that glioblastomas use to escape death.

Comparison of two different radiation fractionation schedules with concurrent chemotherapy in head and neck malignancy.

The worldwide incidence of head and neck malignancy exceeds half a million cases annually. In radiotherapy (RT), conventional fractionation comprises giving five fractions per week from Monday to Friday. Accelerated RT includes administration of six fractions per week is being advocated. It gives better locoregional control and the median overall treatment time is 39 days as compared to 46 days in conventional group. Our study involved comparison of conventional versus accelerated RT with concurrent chemotherapy, in evaluation of local control and toxicity in the two arms. Sixty patients of locally advanced squamous cell carcinoma head and neck region were studied. All the patients received cisplatin (30 mg/m2) weekly during the therapy. The patients received RT dose of 70 Gray (Gy) in 35 fractions (#). The patients were randomly assorted into two groups: Group 1 - Study group (n = 30) - Six fractions RT per week (Monday-Saturday). Group 2 - Control group (n = 30) - Five fractions RT per week (Monday-Friday). During and after the treatment, locoregional control, acute and late radiation toxicity were assessed. Results and Observation: There was no significant difference between the two schedules regarding locoregional control rate. The Grade 3 or higher acute toxicities were significantly higher in the accelerated arm although there was no significant difference in late toxicities between the two arms. Accelerated fractionation regimen was not more efficacious than conventional fractionation in the treatment of previously untreated head and neck carcinoma.

Accelerated Hypofractionated Radiation in Carcinoma Breast

Aim: Comparison of two different radiation fractionation schedules is done in post mastectomy breast cancer cases in relation to loco regional control, acute and late toxicities, survival and overall treatment time (O.T.T). The patient, tumor and treatment related parameters have also been studied. Materials and Methods: Between December 2011 and December 2013, hundred patients of stage II to III carcinoma breast treated with surgery and chemotherapy received adjuvant radiation therapy with two different fractionation regimes: ● (Regimen-1, 50 patients) - 42.5 Gray/16 fractions/3.1 weeks @ 2.6 Gray/ fraction (#) ● (Regimen-2, 50 patients) - 50 Gray/25 fractions/5 weeks @ 2 Gray/fraction (#) Assessment was done for loco regional and distant control rate, acute and late radiation toxicities, and quality of life related parameters. Results: Maximum numbers of patients were of 40-50 year age, post-menopausal, with invasive ductal carcinoma of grade III and stage II or, III. Regimen 1 in comparison to Regimen 2 resulted in comparable loco regional and distant control rate. It also led to significantly less O.T.T. without any significant difference regarding acute and late radiation toxicities. It resulted in significant improvement in patient’s quality of life parameters related to O.T.T. Conclusion: In breast cancer patients undergoing post mastectomy radiotherapy, accelerated hypofractionated radiation (42.5 Gy/16 #/3.1 weeks) in comparison to the conventional radiotherapy (50 Gy/25#/5 weeks) results in comparable loco regional and distant control rates without any significant difference regarding acute and late radiation toxicities. It also leads to significant reduction in overall treatment time with significant improvement in patient’s quality of life parameters related to O.T.T.

A Prospective Study of the Effect of Different Palliative Radiotherapy Fractionation Schedules on Tumor Response and Toxicity in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Background: The optimal dose of palliative radiotherapy (RT) in symptomatic advanced lung cancer is unclear. Patients and methods: Patients with advanced NSCLC who were indicated for thoracic palliative RT with age up to 65 y and Performance Status (PS) 0 - 2 and no significant cardiac or lung co-morbidities were randomized into two fractionation arms: arm A: 30 Gy/10 over 2 weeks and arm B: 27 Gy/6 over 3 weeks (2 fractions per week) using 2 anterior posterior (AP-PA) fields in both arms. Primary end points were symptomatic and radiological tumor response, respiratory functions assessment. Secondary end point was toxicity. Results: From December 2014 to October 2015, 40 patients were randomized, 20 patients in each arm. There was statistically insignificant higher symptomatic improvement in arm B. Four weeks after treatment, 12 out of 40 patients (30%), 6 patients in each arm, had radiological Partial Response (PR) of the primary thoracic lesion without significant difference between the two arms. There was a tendency for improvement in the post treatment mean Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1) in each arm without statistical significance. There were no reported skin reactions or esophagitis in both arms up to 4 weeks after treatment. Eleven out of the 40 patients (27.5%), 6 in arm B and 5 in arm A, had radiological signs of radiation pneumonitis without significant difference between both arms. Conclusion: The two RT fractionation schedules showed equal efficacy in terms of symptoms relief, radiological response of the primary thoracic tumor, respiratory functions and toxicity. Thus the 27 Gy/6 fractionation arm appears preferable compared to 30 Gy/10 arm to minimize the patients’ visits and load on the machines.

Impact of fractionation on out-of-field survival and DNA damage responses following exposure to intensity modulated radiation fields

To limit toxicity to normal tissues adjacent to the target tumour volume, radiotherapy is delivered using fractionated regimes whereby the total prescribed dose is given as a series of sequential smaller doses separated by specific time intervals. The impact of fractionation on out-of-field survival and DNA damage responses was determined in AGO-1522 primary human fibroblasts and MCF-7 breast tumour cells using uniform and modulated exposures delivered using a 225 kVp x-ray source. Responses to fractionated schedules (two equal fractions delivered with time intervals from 4 h to 48 h) were compared to those following acute exposures. Cell survival and DNA damage repair measurements indicate that cellular responses to fractionated non-uniform exposures differ from those seen in uniform exposures for the investigated cell lines. Specifically, there is a consistent lack of repair observed in the out-of-field populations during intervals between fractions, confirming the importance of cell signalling to out-of-field responses in a fractionated radiation schedule, and this needs to be confirmed for a wider range of cell lines and conditions.

Optimization of Radiation Therapy Fractionation Schedules in the Presence of Tumor Repopulation

We analyze the effect of tumor repopulation on optimal dose delivery in radiation therapy. We are primarily motivated by accelerated tumor repopulation toward the end of radiation treatment, which is believed to play a role in treatment failure for some tumor sites. A dynamic programming framework is developed to determine an optimal fractionation scheme based on a model of cell kill from radiation and tumor growth in between treatment days. We find that faster tumor growth suggests shorter overall treatment duration. In addition, the presence of accelerated repopulation suggests larger dose fractions later in the treatment to compensate for the increased tumor proliferation. We prove that the optimal dose fractions are increasing over time. Numerical simulations indicate a potential for improvement in treatment effectiveness.

Palliative radiotherapy fractionation schedules prescribed are dependent on the distance a patient travels to receive treatment

This study assessed the impact of the distance a patient travelled to the treatment centre on the use of single fraction RT for bone metastases. There was significant variability in the prescription of SFRT by distance at which the patient lives from a cancer centre (p<0.001).

Minimizing metastatic risk in radiotherapy fractionation schedules

Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.

OP0009 Comparison of two fractionation schedules on quality of life and survival in patients with brain metastases: A randomised, double-blind trial

Background Different radiation fractionation schedules are used to treat brain metastases. Optimally fractionated radiotherapy is necessary for a highly populated country with limited resources like India. We compared two fractionation schedules in terms of survival and quality of life. Methods 186 patients with radiologically proven brain metastases were randomised (1:1) to receive radiotherapy at 20 Gy in five fractions or 30 Gy in 10 fractions. Results 93 patients were assigned to each group. All patients completed the treatment without interruption. 90% had at least one follow-up visit, and others were telephoned and censored for the survival analysis. Lung cancer was the most common primary cancer and the mean KPS of the population was 70. Median overall survival was comparable between the two groups (88 days versus 85 days). Overall survival at 6 months was 32.3%.The mean technical delay (due to limited resources) in starting radiation was 5.7 days. Better overall survival was noted for patients aged younger than 65 years ( p = 0.02) with good KPS (⩾70; p p = 0.027).Overall survival was also improved for patients who received adjuvant chemotherapy or targeted treatment. Better survival was noted for patients with breast cancer when compared with those with lung cancer (170 days versus 86 days; p = 0.017) and for patients with KPS ⩾70 at presentation. Similarly, patients with fewer than three metastases had better survival ( p = 0.016). Survival analysis by RTOG RPA classes showed better survival for patients in the good prognosis group, although the difference was not significant (class 1: 124 days, class 2: 89 days, class 3: 55 days; p = 0.26). Mean KPS had reduced from 69 to 26 at 6 months. However, KPS in living patients progressively improved at 1, 3, and 6 months (mean 69, 78, and 86 respectively). The improvement in KPS after whole brain radiotherapy was similar in both groups ( p = 0.68). Interpretation In a highly populated country like India with limited resources, 20 Gy in five fractions is a feasible radiotherapy schedule with comparable overall survival and good KPS compared with a longer fractionation schedule. Using this schedule, overall treatment duration could be reduced and more patients can be cared for with available resources.

Single Fraction versus Multiple Fraction Radiotherapy for treatment of painful bone metastases: A Prospective Study; Mansoura experience

Abstract Purpose: Assessment of pain response in patients with bone metastasis after treating with two radiation schedules and to compare toxicity profile in both arms. Patients &amp; Methods: A prospective randomised study was designed to include 100 patients from May 2011 to May 2013. Patients with histopathologically proven primary malignancy having symptomatic secondary deposits to bone were selected for the study. Patients were randomised to 8 Gy in a single fraction (arm A) or 20 Gy in five fractions (arm B). Initial pain response was assessed using numeric rating scale, and compared using the same scale 3 months after completion of treatment. Acute toxicities were assessed using the radiation therapy oncology group criteria for adverse events Results: Arm A comprised 51 patients while 49 patients were enrolled in Arm B. Baseline patient characteristics were comparable. Twelve patients were lost to follow-up. So the 3-month pain score assessment was completed by 88 of the 100 patients; A complete response was observed in 20.4% (18 patients) of the 88 patients, and partial response was observed in 54.5% (48 patients), for an overall response rate of 75% (66 of 88 patients); only 10% (9 patients) of the 88 patients had progression of pain. Mild GI toxicity was noted in both arms but differences in two arms were not statistically significant (p = 0.45), no interruption of treatment was required because of side effects. Conclusions: In our study, we found both the radiation fractionation schedules for palliative bone metastasis treatment is equally effective in pain control.

Patient’s Choice of Radiotherapy Fractionation Schedule in Early Staged Post Breast Conserving Surgery: Design and Validation of a Decision Board

Patient’s Choice of Radiotherapy Fractionation Schedule in Early Staged Post Breast Conserving Surgery: Design and Validation of a Decision Board

Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution

BackgroundThe optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients.MethodsAll data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled. Clinical information was collected using patient charts and government registry. Cox analysis was used to identify variables affecting survival and treatment outcome.ResultsThe median follow-up time was 13.2 months. Two hundred and seventy-six patients met the inclusion criteria, including 147 patients in the 60 Gy in 30 fractions (ConvRT) group, 86 patients in the 60 Gy in 20 fractions (HF60) group, and 43 patients in the 40 Gy in 15 fractions (HF40) group. Median survival (MS) was 16.0 months with a median progression-free survival (PFS) of 9.23 months in the ConvRT group. This was comparable to outcome in the HF60 group with MS 15.0 months and a median PFS of 9.1 months. Patients in the HF40 group had MS of 8 months, with a median PFS 5.4 months. Cox analysis showed no significant difference in OS between the ConvRT and HF60 groups but worse outcome in the HF40 group (HR 2.22, P = 0.04). MGMT methylation, extent of resection, use of chemotherapy, and repeat surgery were found to be significant independent prognostic factors for survival.ConclusionsHF60 constitutes a safe RT approach that shows survival comparable to standard RT while allowing for a shorter treatment time.