Hypofractionated Radiation Treatment Research Articles

Predictive Value of Tumor Volume on Local Control in Hepatocellular Carcinoma Treated with Image Guided Hypofractionated Radiation Treatment

External beam radiation treatment (EBRT) is an important local treatment in liver-confined hepatocellular carcinoma (HCC) patients who are not candidates for curative therapy. EBRT dose, technique and prognostic factors are evolving. We hypothesized that tumor volume to liver volume ratio can be a predictor of local control (LC) in patients treated with hypo-fractionated radiation (HFRT) in HCC MATERIALS/METHODS: We retrospectively reviewed 50 patients of HCC treated with HFRT at our institution. HFRT schedule was chosen such that the radiation dose to the remaining liver and other organs at risk (OAR) met the standard dosimetric constraints. Image guided techniques were used for motion management, internal target volume (ITV) and planning target volume (PTV) delineation. Tumor to Liver Ratio (TLR) was defined as ratio of PTV volume to whole liver volume. TLR ≤ 0.3 was considered as low volume disease and TLR > 0.3 was considered as high-volume disease. The radiation dose ranged from 45 Gy to 67.5 Gy in 5 - 15 fractions. The biologically equivalent dose (BED) for tumor ranged from 58.5 Gy10 to 100 Gy10. Local control (LC) was evaluated by Kaplan-Meier analysis, with log-rank test for groups stratified as per TLR. Multivariate Cox regression analysis was performed to identify additional prognostic factors. The mean duration of follow-up was 24 months. The median age was 69 years (range 50 - 90) and 76% were males. 32 patients had CP-A class cirrhosis while 17 had CP-B and 1 had CP-C class. BCLC stage A, B, C and D was seen in 2, 14, 33 and 2 patients, respectively. Portal vein thrombosis was present in 9 patients and prior trans-arterial chemo embolization (TACE) was done in 23 patients. The median volume of PTV was 551 cc (range 52 - 1990 cc). The TLR ranged from 0.04 - 0.67 with a median of 0.29. The median BED radiation dose was 78.4 Gy10 (range - 58.5 Gy10 to 100 Gy10). Nine patients had local recurrence with overall LC rate of 82%. The LC was better in low volume tumors, with the TLR cut-off of 0.3 as a significant factor associated with LC (p = 0.007). The 1-year actuarial LC with TLR ≤ 0.3 was 88% as compared 61% in TLR of > 0.3 (p = 0.007). BED ≥60 Gy10 was associated with better 1 year LC as compared to BED < 60 Gy10 (89% vs 62%; p = 0.11). ALBI grade 1 was associated with better 1 year LC as compared to ALBI grade 2 (80% versus 75%; p = 0.40). On multivariate analysis, high volume disease and TLR >0.3 were significant prognostic factor for LC. HFRT has good 1-year local control of 82% in carefully selected unresectable HCC. Radiation with BED greater than 60 Gy10 and ALBI grade 1 showed a trend towards better LC. Smaller tumors had better LC with a PTV to liver ratio (TLR) of < 0.3. This information can help in identifying the poor responders, intensifying the radiation treatment and adding additional therapy to improve the oncological outcomes.

Aspects of hypofractionation in modern radiation oncology

Background. In the modern world, the incidence of cancer diseases is rapidly increasing and is the second most common cause of death. This is preconditioned by the quantitative growth of the senior and elderly population, as well as the growth of the main risk factors for cancer, which is related to the socio-economic development of society. About half of cancer cases require radiation therapy (RT) as a component of multimodal treatment, therefore its improvement, namely the introduction of hypofractionated radiation regimens, is considered today as one of the most effective ways to increase availability of oncological care and optimize the use of health care system resources.&#x0D; Purpose. To find out clinical and medico-social advantages of the hypofractionated approach in radiation oncology in order to optimize the functioning of the health care system by increasing availability of treatment for cancer patients. To highlight the importance of hypofractionated RT in terms of evidence-based medicine for the most common oncological pathology and in neuro-oncology. To demonstrate the influence of the COVID-19 pandemic on the implementation of hypofractionated RT. To present our own experience of using hypofractionated radiation regimens in patients with glioblastoma (GB).&#x0D; Materials and methods. MEDLINE (Pubmed), EMBASE (Ovid), Web of Science (Web of Knowledge) databases were used to search for literature. The search was performed in the English-language sources with the following keywords: «Radiation», «Hypofractionation radiotherapy», «Hypofractionated radiotherapy», «Hypofractionated irradiation»; «Breast cancer»; «Prostate cancer»; «Lung cancer»; «Glioblastoma», COVID-19. Systematic reviews, meta-analyses, randomized controlled trials and retrospective clinical trials were reviewed in full. The primary sources were backreferenced to identify additional relevant studies related to hypofractionated radiation treatment regimens. The last date of the search is 05.25.2023. The authors’ own experience of the hypofractionated approach in the adjuvant radiation treatment of patients with GB is presented briefly, as a reflection of the relevance of the authors’ practical experience to the provisions of the narrative review, based on the results of a retrospective single-center non-randomized study conducted at the State Institution «Romodanov Neurosurgery Institute National Academy of Medical Sciences of Ukraine» in 2014–2020. The oncological results of 110 (69.2%) patients of the hypofractionated RT group (15 fractions, single fraction dose (SFD) 3.5 Gy, total fraction dose (TFD) 52.5 Gy) and 49 (30.8%) patients of the standard RT group (30 fractions, RVD 2.0 Gy, SVD 60.0 Gy) were compared. RT was performed with Trilogy linear accelerator (USA) (6 MeV) using the intensity-modulated radiotherapy method (IMRT). Overall survival (OS) and recurrence-free survival (RFS) in the groups were analyzed.&#x0D; Results and discussion. Hypofractionated approaches, which allow to significantly decrease the duration of radiation treatment, have clinical, medical and social advantages, including: increased comfort for a patient; reduction of the workload on staff and technological equipment of medical facilities; reduction of the cost of treatment. The introduction of hypofractionated RT allows to increase access to cancer care at the global level, reducing disparity in the results of treatment of cancer patients between low- and middle-income countries and the countries with high income level. Hypofractionated radiation regimens are included in the clinical guidelines of professional associations, as for the most common forms of cancer and for malignant brain tumors, and represent the standard of treatment for particular clinical cases. Our experience of using the hypofractionated radiation regimen is based on the adjuvant radiation treatment of 110 patients with GB and in terms of clinical results is a relevant concept presented in a narrative review. The analysis showed no statistical difference between the groups of standard fractionation and hypofractionated RT in OS (Logrank test p = 0.06757) and RFS (Logrank test p = 0.43374). In the hypofractionation group, with an observation time median of 22.3 months, the OS median was 16.5 (95% CI 14.1–18.8) months; median RFS was 9.0 (95% CI 8.0–10.0) months. In the standard radiation regimen group, with a median of observation time of 24.4 months, the median OS was 15.0 (95% CI 14.1–17.1) months; median RFS is 9.0 (95% CI 9.0–10.0) months.&#x0D; Conclusion. Development and implementation of the measures designed to optimize the use of resources of medical facilities of Ukraine is a necessary condition for maintaining high-quality care for cancer patients in the conditions of full-scale military aggression, which has been ongoing since February 24, 2022. Increased application of hypofractionated approaches in radiation oncology can be considered as a potential tool for optimization of the use of resources of the healthcare system of Ukraine and enhancing public health.

Moderate hypofractionated radiation therapy and pathologic response for soft tissue sarcomas (STS) of limbs and trunk: experience from a tertiary cancer center.

Preoperative radiation therapy following by limb-sparing or conservative surgery is a standard approach for limb and trunk STS. Data supporting hypofractionated radiotherapy schedules are scarce albeit biological sensitivity of STS to radiation would justify it. We sought to evaluate the impact of moderate hypofractionation on pathologic response and its influence on oncologic outcomes. From October 2018 to January 2023, 18 patients with limb or trunk STS underwent preoperative radiotherapy at a median dose of 52.5Gy (range 49.5-60Gy) in 15 fractions of 3.5Gy (3.3-4Gy) with or without neoadjuvant chemotherapy. A favorable pathologic response (fPR) was considered as ≥ 90% tumor necrosis on specimen examination. All patients completed planned preoperative radiotherapy. Eleven patients (61.1%) achieved a fPR, and 7 patients (36.8%) a complete pathologic response with total disappearance of tumor cells. Nine patients (47%) developed grade 1-2 acute skin toxicity, and 7 patients (38.8%) had wound complications on follow-up. With a median follow-up of 14months (range 1-40), no cases of local relapse were observed, and actuarial 3-year overall survival (OS) and distant metastases-free survival (DMFS) are 87% and 76.4%, respectively. In the univariate analysis, the presence of a favorable pathologic response (fPR) was associated with improved 3-year OS (100% vs. 56.03%, p = 0.058) and 3-year DMFS (86.91% vs. 31.46%, p = 0.002). Moreover, both complete or partial RECIST response and radiological stabilization of the tumor lesion showed a significant association with higher rates of 3-year distant metastasis-free survival (DMFS) (83% vs. 83% vs. 56%, p < 0.001) and 3-year overall survival (OS) (100% vs. 80% vs. 0, p = 0.002). Preoperative moderate hypofractionated radiation treatment for STS is feasible and well tolerated and associates encouraging rates of pathologic response that could have a favorable impact on final outcomes.

Comparative evaluation of hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate and high risk prostate cancer.

The purpose of this study was to comparatively evaluate an efficacy and toxicity profile of hypofractionated radiotherapy (67.5 Gy in 25 fractions) to conventionally fractionated radiotherapy (78 Gy in 39 fractions) in prostate cancer patients with intermediate and high-risk disease. From January 2015 to December 2018, 168 patients were randomized to hypofractionated radiation treatment and conventional fractionated radiation treatment schedules of volumetric modulated arc therapy (VMAT) to the prostate and seminal vesicles. All the patients also received androgen deprivation therapy (ADT) and radiation therapy started after ADT. The median (range) follow-up was 51 (31-63) and 53 (33-64) months in the hypofractionated and conventionally fractionated regimes, respectively. The 3-year biochemical no evidence of disease (bNED) rates were 86.9% and 73.8% in the hypofractionated and conventionally fractionated groups, respectively (p = 0.032, significant). The 3-year bNED rates in patients at a high risk [i.e., pretreatment prostate-specific antigen (PSA) > 20 ng/mL, Gleason score ≥ 8, or T ≥ 2 c], were 87.9% and 73.5% (p = 0.007, significant) in the hypofractionated and conventionally fractionated radiotherapy groups, respectively. No statistically significant difference was found for late toxicity between the two groups, with 3-year grade 2 gastrointestinal toxicity rates of 19% and 16.7% and 3-year grade 2 genitourinary toxicity rates of 15.5% and 11.9% in the hypofractionated and conventionally fractionated radiotherapy groups, respectively. Hypofractionated schedule is superior to the conventional fractionation schedule of radiation treatment in terms of bNED in intermediate and high grade prostate cancer patients. Also, the late toxicity is found to be equivalent between the two treatment groups.

Conventional vs. Hypofractionated, Radiotherapy for High-Risk Prostate Cancer: 7-Year Outcomes of the Randomized, Non-Inferiority, Phase 3 PCS5 Trial

<h3>Purpose/Objective(s)</h3> The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients only, and present the pre-planned analysis of efficacy at seven years (Prostate Cancer Study number 5: PCS5) <h3>Materials/Methods</h3> PCS5 is a Canadian multi-centric, non-inferiority phase III trial of intensity-modulated conventionally fractionated radiation therapy (CFRT) vs. HFRT in men with high-risk PCa as per NCCN definition. From Feb. 2012 to Mar. 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. Participants were analyzed as per intention-to-treat. <h3>Results</h3> Of the 329 patients, 164 were randomized to HFRT and 165 to CFRT. Of these, 159 men in the hypofractionation arm and 160 in the standard arm were included in survival analyses. At 7 years of follow up there were no significant differences in survival between HFRT and CFRT for overall mortality (81.7% vs. 82%; HR 0.92 [0.56-1.53]; CI:95%; p=0.76), prostate cancer specific mortality (94.9% vs. 96.4%; HR 1.31 [0.46-3.78]; CI:95%; p=0.61), biochemical recurrence (87.4% vs. 85.1%; HR 0.89 [0.49-1.60]; CI:95%; p=0.69), distant metastatic recurrence (91.5% vs. 91.8%; HR 0.89 [0.41-1.90]; CI:95%; p=0.76), or disease free survival, respectively (either biochemical or distant recurrence) (86.5% vs. 83.4%; HR 0.82 [0.47-1.46]; CI:95%; p=0.50). The Relative Risks were close to 1.00 for all outcomes at 3-, 5-, and 7-years after treatment, with very tight bootstrapped confidence intervals, suggesting equivalent risks for all outcomes in both study arms. There were no significant differences in grade 3 or higher acute and delayed genitourinary (GU) and gastrointestinal (GI) toxicities at 2 years and no new toxicities emerged thereafter. There were no grade 4 toxicities in either arm. <h3>Conclusion</h3> This is the first hypofractionated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Hypofractionated radiotherapy using 68 Gy in 25 fractions is non-inferior to conventional fractionation using 76Gy in 38 fractions and can be considered as a new standard of care for external-beam radiotherapy of high-risk prostate cancer.

Prognostic Impact of Biologically Equivalent Dose in Stereotactic Body Radiation Therapy for Renal Cancer

Surgical resection is standard of care for initial management of localized renal cell cancer (RCC). Stereotactic body radiation therapy (SBRT) is an emerging therapy that has seen increased utilization for unresectable RCC. Due to the low α/β ratio of RCC, an improved therapeutic ratio would be predicted with the use of hypofractionated radiation treatment. While different SBRT fractionation schemes are utilized with a wide range of biologically equivalent dose (BED) for management of RCC, there is an absence of data evaluating the prognostic impact of BED for disease control.The National Cancer Database (NCDB) was queried (2004-2017) for patients with RCC (ICD C64.9) who did not have surgical resection but received definitive SBRT (defined as > 400 cGY/ fraction) to the kidney. BED was calculated using an α/β ratio of 3. Patients with a BED3 > 60 Gy were included. Kaplan-Meier analysis with log-rank test was used to evaluate overall survival (OS). Univariable (UVA) and multivariable (MVA) analysis were conducted using cox proportional hazard models to determine which clinical and treatment factors were prognostic for overall survival.A total of 344 patients with median age 77 (IQR 70 - 85) were included in this study. Histology was clear cell in 72.7%, papillary in 6.4%, transitional in 14.2%, and other/unknown in 6.7%. T stage was cT1a in 46.8%, cT1b in 25.9%, cT2 in 4.9%, cT3 in 6.1%, and cT4 in 1.2%. A total of 2.3% of patients were cN1, 6.1% of patients were cM1, and 7% received systemic therapy either before (72.7%), after (22.7%), or concurrent (4.5%) with radiation. Median BED3 was 180 Gy (IQR 126.03 - 233.97). Median OS was 90 months in the highest quartile compared to 36 - 52 months in the lower three quartiles (P = 0.007). On UVA, higher BED3 was a positive prognostic factor both as a continuous variable (HR 0.99, P = 0.001; CI 0.99 - 0.99) and as a categorical variable when stratifying patients by a BED3 of 180 Gy (HR 0.67, P = 0.008; CI 0.51 - 0.91). On MVA, higher BED3 measured as a continuous variable (HR 0.97, P = 0.005; CI 0.95 - 0.99) was a positive prognostic factor, while age (HR 1.03, P = 0.005; CI 1.01 - 1.04), transitional cell histology (HR 2.49, P = 0.004; CI 1.34 - 4.64), T stage (cT1b) (HR 1.69, P = 0.009; CI 1.14 - 2.51), and M stage (HR 14.01, P < 0.001; CI 5.90 - 33.27) were negative prognostic factors.This is the first study investigating the prognostic impact of BED for renal cancer SBRT. Higher BED is associated with improved OS. Prospective investigation is needed to clearly define optimal BED for SBRT used to treat RCC.

External Validation of Pulmonary Toxicity Risk Model for Ultracentral Lung Tumors

Pulmonary toxicity attributed to the proximal bronchial tree (PBT) is dose-limiting in stereotactic body radiation therapy (SBRT) for central lung tumors. The toxicity is of particular concern in ultracentral lesions, which are defined as the gross tumor volume abutting the PBT, esophagus, or other mediastinal structures. In this work we tested published pulmonary toxicity models associated with dose to the airway structures after SBRT for ultracentral tumors in an independent institutional cohort of patients.The PubMed database was scrutinized for toxicity models evaluating pulmonary and airway toxicity for SBRT or hypofractionated radiation treatment for central tumors in the lung. The following search term criteria were used: (central) AND (lung tumor) AND (normal tissue complication probability) AND (radiation). Identified models were explored in all patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60% primary lung and 40% metastatic patients that had been treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx. 16% of the patients received anti-VEGF therapy, which as previously shown, was associated with higher incidence of grade 5 hemorrhage.A total of six NTCP models were identified from work by Tekatli et al 2018. Of these, three models were for ≥grade 3 and three for grade 5 toxicity and included bronchial max dose, V60, V100, and V130. Clinical pulmonary toxicity consisted of radiation pneumonitis, atelectasis due to main stem bronchus occlusion, and/or hemoptysis. The pulmonary toxicity rate was 15% and 8% for ≥grade 3 toxicity and grade 5 toxicity, respectively, in the original study. Within the independent cohort, the corresponding values were 18% and 10%. Two maximum dose models were shown to be valid in our institutional dataset; other models failed this validation test. The model was made more robust by expanding the max dose region of the bronchial volume by focusing on the max dose to 0.1 cm3, 1 cm3 and 3 cm3. The max dose (0.1 cm3) model had improved performance with increased steepness. Generally, models from literature underestimated our institutional complication rates.Pulmonary toxicity models for central tumors were identified from one study and explored within an independent cohort. The models derived from primarily central lung tumors systematically underestimated the pulmonary toxicity rate in the solely ultracentral tumor cohort, possibly also due to anti-VEGF therapy used in the independent cohort. A modified model from the best-performing max dose model was designed, and this model could be utilized for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation.I. Chen: None. M. Thor: None. A.J. Wu: Research Grant; CivaTech Oncology, Inc. Honoraria; 1199SEIU. Consultant; AstraZeneca, MORE Health. Advisory Board; Simphotek, Inc. Travel Expenses; AlphaTau Medical. Stock; Simphotek, Inc. A. Iyer: None. A. Apte: None. A. Rimner: Research Grant; Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Pfizer, Merck. Consultant; MoreHealth. Advisory Board; Boehringer Ingelheim, Astra Zeneca, Merck; International Thymic Malignancies Interest Group, International Mesothelioma Interest Group. D.R. Gomez: Research Grant; Merck, AstraZeneca. Honoraria; BMS, Varian, Research to Practice. Speaker's Bureau; Merck. Advisory Board; AstraZeneca, Olympus. J.O. Deasy: Research Grant; Varian Corp., NIH, Breast Cancer Research Foundation. Stock; Paige.AI; AAPM.A. Jackson: None.

Bronchiolitis Obliterans Organizing Pneumonia after Breast Cancer Radiotherapy and letrozole: A Case Report and Literature Review

Objectives: Bronchiolitis obliterans organizing pneumonia occurs with prevalence rate 1–3% after breast conservative treatment in series. In response to radiation of a lung or surrounding tissues, an inflammatory reaction can affect both lungs and is located within the radiation field. Characteristic imaging features include multiple alveolar opacities and diffuse ground-glass shadows. Letrozole may induce iatrogenic organizing pneumonia. Materials and methods: we report the case of a 76-year-old female who underwent conservative treatment for an invasive ductal carcinoma of the left breast. Hypofractionated radiotherapy was delivered with a total dose of 42.5 Gy in 16 sessions of 2.65 Gy using a three-dimensional technique. After the radiotherapy ended letrozole was indicated. Results: Several weeks after the radiotherapy ended and letrozole was introduced, she described a flu-like syndrome. Samples were negative, and there was no improvement after four courses of antibiotics. Imaging suggested bronchiolitis obliterans organizing pneumonia. Her symptomatology lessened after the letrozole was discontinued, and 11 months after radiotherapy finished, her imaging results were clear. Conclusion: Physicians must consider bronchiolitis obliterans organizing pneumonia. Cases may increase with hypofractionated radiation treatment and new drugs. Letrozole may potentiate the risk. Dosimetry may be adapted to the lung and subpleural areas for patients with risk factors and taking adjuvant or concurrent drugs with potential pneumotoxicity.

Bronchiolitis Obliterans Organizing Pneumonia after Breast Cancer Radiotherapy and letrozole: A Case Report and Literature Review

Objectives: Bronchiolitis obliterans organizing pneumonia occurs with prevalence rate 1–3% after breast conservative treatment in series. In response to radiation of a lung or surrounding tissues, an inflammatory reaction can affect both lungs and is located within the radiation field. Characteristic imaging features include multiple alveolar opacities and diffuse ground-glass shadows. Letrozole may induce iatrogenic organizing pneumonia. Materials and methods: we report the case of a 76-year-old female who underwent conservative treatment for an invasive ductal carcinoma of the left breast. Hypofractionated radiotherapy was delivered with a total dose of 42.5 Gy in 16 sessions of 2.65 Gy using a three-dimensional technique. After the radiotherapy ended letrozole was indicated. Results: Several weeks after the radiotherapy ended and letrozole was introduced, she described a flu-like syndrome. Samples were negative, and there was no improvement after four courses of antibiotics. Imaging suggested bronchiolitis obliterans organizing pneumonia. Her symptomatology lessened after the letrozole was discontinued, and 11 months after radiotherapy finished, her imaging results were clear. Conclusion: Physicians must consider bronchiolitis obliterans organizing pneumonia. Cases may increase with hypofractionated radiation treatment and new drugs. Letrozole may potentiate the risk. Dosimetry may be adapted to the lung and subpleural areas for patients with risk factors and taking adjuvant or concurrent drugs with potential pneumotoxicity.

A Comparative Study of the Recurrence Rate in Hypofractionated versus Conventional Postmastectomy Radiation in Breast Cancer

Background: Treatment options available for breast cancer are Surgery [Breast conservation surgery (BCS) or Modified radical mastectomy (MRM)]; Radiation treatment [Conventional radiation treatment or CRT and Hypofractionated radiation treatment or HRT] and Chemotherapy. In the postmastectomy or post lumpectomy setting, radiotherapy (RT) improves loco-regional control. CRT for breast includes 50 Gy in 25 fractions (2 Gy per fraction) and HRT includes 42.5 Gy in 16 fractions (2.7 Gy per fraction) or extreme hypofractionation like 26 Gy in 5 fractions. Alpha/beta value for breast is less, so HRT is ideal for breast. So, there will be good loco-regional control, without increased normal tissue damage. This study aims to identify recurrence rate and toxicity in breast cancer patients treated using conventional and hypofractionated postmastectomy radiotherapy among Indian population. Primary objective: To assess recurrence rate of disease in breast cancer patients treated using hypofractionated postmastectomy radiation and to compare it with breast cancer patients treated using conventional postmastectomy radiation. Secondary objective: To assess the toxicity in hypofractionation and conventional fractionation arm. Methods: This is a prospective observational study conducted in Department of Radiation Oncology from December 2017 to June 2019. Radically treated breast cancer patients who received radiation treatment either conventional or hypofractionated as one of the treatment modalities were included in the study. Data were collected using a structured proforma, history and physical examination, master file of the patients, lab results and the imaging reports, written informed consent form, ECOG performance status scale (Eastern Cooperative Oncology Group), RTOG (Radiation Therapy Oncology Group) Acute Radiation Morbidity Scoring Schema. Patients were monitored for 18 months to identify recurrence rate and toxicity in each arm. Results and discussion: A total of 241 patients were enrolled into this study, among them 175 patients (73%) were given hypofractionation radiotherapy and 66 patients (27%) were given conventional radiotherapy. In hypofractionation arm, recurrence was found in 14 patients (8%), of which, 3 were local recurrences [chest wall] and 11 were systemic recurrences, while in conventional arm, recurrence was found in 4 patients (6%) and all of them were systemic recurrences. Recurrence rate in hypofractionation arm was 8% and in conventional arm was 6.10%. The Kaplan Meier curve shows no significant difference between the two arms with p value = 0.76. Acute toxicities assessed were dermatitis, esophagitis and pneumonitis. Among acute dermatitis, 4 patients had grade 3 and 2 patients had grade 4 in hypofractionation arm, while in conventional arm, 7 patients had grade 3 and 1 patient had grade 4. Grade 1 and 2 together versus grade 3 and 4 acute dermatitis showed a statistically significant difference between the two arms, with more acute toxicity in the conventional arm. Among acute esophagitis, 1 patient had grade 3 and no patients had grade 4 in hypofractionation arm; while in conventional arm, no grade 3 and grade 4 acute esophagitis were found. Among acute pneumonitis, 2 patients had grade 3 and 1 patient had grade 4 in hypofractionation arm, while in conventional arm, 1 patient had grade 3 and no patients with grade 4 were found. Grade 2 and grade 3 acute lung toxicities were found in patients with central lung distance more than 1.5 cm. Conclusion: It was found that the recurrence rate of hypofractionation radiotherapy was comparable to conventional fractionation radiotherapy. With respect to acute dermatitis, grade 1 and grade 2 were significantly more in conventional than hypofractionation arm. Hypofractionated radiotherapy is an equally effective option to conventional radiotherapy and should be encouraged, especially for developing countries like India where the resource is limited, and the incidence of tumour is high.

Long-term results from a series of patients managed with breast conservation surgery and hypofractionated radiotherapy in Christchurch: What is the recurrence rate and how do we detect recurrences.

Hypofractionated radiation treatment (HFRT) following breast conservation surgery (BCS) has similar efficacy to conventionally fractionated radiation treatment (CFRT). This study updates outcomes for patients treated with HFRT in Christchurch, New Zealand, and reports on the pattern, timing and method of detection of recurrences to inform follow-up practice. Between 2004 and 2006, 273 women with early breast cancer were treated with HFRT (42.5 Gray (Gy) in 16 fractions). Details of demographics, tumour characteristics, treatments, any recurrence (local, nodal or distant), follow-ups and date of death were collected. The primary endpoint was local recurrence rate (LRR); secondary endpoints were local recurrence-free survival (LRFS) and overall survival (OS). With a median follow-up of 12.9years, 17 women developed a local recurrence. LRR at 5 and 10years were 3.1% and 5.3%, respectively. Five-year LRFS was 91.7% and ten-year LRFS was 83.5%. The OS at five years was 93.7% and at ten years was 87.7%. For the 41 patients with a first recurrence at any site, 75.6% were symptomatic, 22% were screen detected with radiology and 2.4% were incidental findings. None of the first recurrences were detected when asymptomatic on clinical examination in follow-up clinics. The rate of local recurrence following HFRT for BCS is low. No asymptomatic recurrence was detected by routine clinic follow-up. The utility of regular clinical examination for the detection of recurrence is low and this should inform follow-up strategies.

Three-dimensional surface imaging in breast cancer: a new tool for clinical studies?

BackgroundThree-dimensional Surface Imaging (3DSI) is a well-established method to objectively monitor morphological changes in the female breast in the field of plastic surgery. In contrast, in radiation oncology we are still missing effective tools, which can objectively and reproducibly assess and document adverse events in breast cancer radiotherapy within the framework of clinical studies. The aim of the present study was to apply structured-light technology as a non-invasive and objective approach for the documentation of cosmetic outcome and early effects of breast radiotherapy as a proof of principle.MethodsWeekly 3DSI images of patients receiving either conventionally fractionated radiation treatment (CF-RT) or hypofractionated radiation treatment (HF-RT) were acquired during the radiotherapy treatment and clinical follow-up. The portable Artec Eva scanner (Artec 3D Inc., Luxembourg) recorded 3D surface images for the analysis of breast volumes and changes in skin appearance. Statistical analysis compared the impact of the two different fractionation regimens and the differences between the treated and the contralateral healthy breast.ResultsOverall, 38 patients and a total of 214 breast imaging sessions were analysed. Patients receiving CF-RT showed a significantly higher frequency of breast erythema compared to HF-RT (93.3% versus 34.8%, p = 0.003) during all observed imaging sessions. Moreover, we found a statistically significant (p < 0.05) volumetric increase of the treated breast of the entire cohort between baseline (379 ± 196 mL) and follow-up imaging at 3 months (437 ± 224 mL), as well as from week 3 of radiotherapy (391 ± 198 mL) to follow-up imaging. In both subgroups of patients undergoing either CF-RT or HF-RT, there was a statistically significant increase (p < 0.05) in breast volumes between baseline and 3 months follow-up. There were no statistically significant skin or volumetric changes of the untreated healthy breasts.ConclusionsThis is the first study utilizing 3D structured-light technology as a non-invasive and objective approach for the documentation of patients receiving breast radiotherapy. 3DSI offers potential as a non-invasive tool to objectively and precisely monitor the female breast in a radiooncological setting, allowing clinicians to objectively distinguish outcomes of different therapy modalities.

Hypofractionated radiation treatment for breast cancer: The time is now.

While there is now Level I data with long-term follow-up supporting the routine use of hypofractionated (HF) whole-breast radiation therapy (WBRT) after breast-conserving surgery, its adoption has been slow and variable. This article will review the literature supporting the efficacy and safety of hypofractionated radiation for breast cancer, discuss the radiobiological rationale specific to breast tumors, and make an argument for justifying the routine adoption of shorter, HF-WBRT courses when delivering breast radiation. Data using HF with regional nodal irradiation and in the post-mastectomy setting will also be reviewed. The aim is to provide an in-depth understanding of the use of hypofractionated radiation therapy for breast cancer, its applicability, and topics warranting future research.

A Prospective Study of Cosmetic Outcomes for Patients Treated with Breast Conservation and Radiation Therapy using Shorter Fractionation Schedules at Auckland Hospital, New Zealand

AimsBreast cosmesis is an important outcome for women after breast conservation. It has been shown to be correlated with better patient satisfaction, sexuality and self-esteem. This study reports the subjective and objective breast cosmesis outcomes for women treated at Auckland Hospital Radiation Oncology Department using hypofractionated radiation therapy. Materials and methodsBreast cosmesis was evaluated using a subjective questionnaire and standardised photographs before radiation, at 6 weeks, 1 year, 3 years and 5 years after radiation. Objective evaluation of the photographs and completion of questionnaires were undertaken by clinicians at the same time points. The questionnaire evaluated global cosmesis on a four-point scale – excellent (E), good (G), fair (F) and poor (P). Patient, tumour and treatment factors were evaluated to assess the impact on cosmesis. ResultsThree hundred and fifty-eight patients completed the baseline assessments and two hundred and two patients completed the 5-year assessments. Sixty-eight per cent of patients at baseline and 70% at 5 years scored their cosmesis as E/G compared with 52% and 51%, respectively, by clinician assessment. Age >50 years, separation ≤25 cm, non-diabetic, T1 tumours, node negative, quadrant of the scar, no boost and no adjuvant endocrine therapy were correlated with E/G cosmesis. On multivariate analysis at baseline, the individual breast factors that were significantly associated with a score of E/G cosmesis were breast shape (P = 0.028) and scar appearance (P = 0.001). At 5 years, breast shape (P = 0.003), nipple shape (P = 0.019) and scar appearance (P = 0.001) were found to be significant. ConclusionThis study shows that most women reported no significant change in their breast cosmesis after hypofractionated radiation treatment over 5 years and that a number of patient, tumour and treatment factors may impact on breast cosmesis.

Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma.

Objective:Recent research has shown that combining radiotherapy and immunotherapy can counteract the ability of cancer to evade and suppress the native immune system. To optimise the synergy of the combined therapies, factors such as radiation dose and fractionation must be considered, alongside numerous parameters resulting from the complexity of cancer–immune system interactions. It is instructive to use mathematical models to tackle this problem.Methods:In this work, we adapted a model primarily to describe the synergistic effect between single-fraction radiotherapy and immunotherapy (1-methyl tryptophan) observed in previous experiments with glioblastoma-carrying rats. We also showed how the model can be used to generate hypotheses on the outcome of other treatment fractionation schemes.Results:The model successfully reproduced the results of the experiments. Moreover, it provided support for the hypothesis that, for a given biologically effective dose, the efficacy of the combination therapy and the synergy between the two therapies are favoured by the administration of radiotherapy in a hypofractionated regime. Furthermore, for a double-fraction irradiation regimen, the synergy is favoured by a short time interval between the treatment fractions.Conclusion:It was concluded that the model could be fitted to reproduce the experimental data well within its uncertainties. It was also demonstrated that the fitted model can be used to form hypotheses to be validated by further pre-clinical experiments.Advances in knowledge:The results of this work support the hypothesis that the synergetic action of combined radiotherapy and immunotherapy is favoured by using a hypofractionated radiation treatment regimen, given over a short time interval.

Cost-containment in hypofractionated radiation therapy: a literature review.

Recent technological advances in radiation therapy have allowed for greater accuracy in planning and treatment delivery. The development of hypofractionated radiation treatment regimens is an example, and has the potential to decrease the cost per episode of care, relative to conventional treatments. Our aim was to analyse published literature on the cost‐effectiveness and budgetary implications of hypofractionated radiation therapy. As such, this article will quantify the projected health care cost savings and address the optimal means of treatment delivery, associated patient outcomes, and implications arising from an increased use of hypofractionated regimens.

Hypofractionated, dose escalation radiotherapy for high-risk prostate cancer: The primary endpoint of a group led phase III trial. (PCS5).

123 Background: The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients and present the primary safety analysis of side effects at 2 years. Methods: We conducted a Canadian multi-centric phase III trial of conventional fractionated radiation therapy (CFRT) vs. intensity-modulated HFRT in men with high-risk PCa as per NCCN definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. The primary endpoint was to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. Results: Of the329 patients, 164 were randomized to HFRT and 165 to CFRT. The minimum, median and maximum follow-up were 24, 40 and 60 months respectively. At 24 months, 12 patients in the CFRT arm and 15 patients in the HFRT arm had grade 2 or worse gastrointestinal (GI)-related adverse events (HR:1.32 [0.62.2.83] 95% CI; P=NS). Similarly, 11 patients in the CFRT arm and 3 patients in HFRT arm had grade 2 or higher genitourinary (GU) toxicities (HR:0.26 [0.07-0.94] 95% CI; P=0.037). In the HFRT arm, there were 3 grade 3 GI and one grade 3 GU related toxicities. In the CFRT arm there were 3 grade 3 GU and no grade 3 GI related toxicities. There were no grade 4 toxicities in either arm. Conclusions: This is the first hypofractionated dose escalated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Our results indicate that moderate HFRT to high risk PCa patients is equally well tolerated as CFRT at 2 years. Clinical trial information: NCT01444820.

Ischaemic heart disease following conventional and hypofractionated radiation treatment in a contemporary breast cancer series.

We report the incidence of ischaemic cardiac toxicity in a contemporary cohort of patients receiving conventional (CFRT) or hypofractionated (HFRT) radiation after surgery for early breast cancer and investigate the interplay of cardiac risk factors and fractionation. Included were patients receiving external beam radiation treatment from 2002 to 2006 at the Christchurch public hospital. Hospital coding databases, oncology databases and medical records were reviewed for baseline characteristics, treatment details and outcomes. The primary outcome was cardiac toxicity (including myocardial infarction, admission for cardiac chest pain, coronary angiogram positivity and ischaemic cardiac death). Kaplan-Meier methods were used to derive ischaemic cardiac event free and overall survival. Predefined univariate and multivariate analysis was performed to investigate interaction with radiation fraction size, cardiac risk factors, age and side of cancer. Standardised mortality ratios were constructed. Five hundred and one patients were identified, 220 treated with CFRT and 281 with HFRT. The median age was 56 and median follow-up 10.33 years. The 10-year breast cancer specific survival was 81.8% (95% CI %.78.1-85.0). The 10-year freedom from cardiac death was 98.6% (95% CI 96.9-99.4). There were 27 post radiation cardiac events including 5 cardiac deaths and 19 cases of acute myocardial infarction. 265 (53%) had at least one cardiac risk factor. Twenty five of the 27 patients with a cardiac event had cardiac risk factors. On univariate and multivariate analysis, fractionation schedule was not significantly associated with a post radiation ischaemic event, however, there was a significant relationship with age and the presence of a cardiac risk factor. The standardised mortality ratio was 0.89 (95% CI: 0-3.13). Our study has shown a low rate of ischaemic cardiac disease for both CFRT and HFRT in women treated for breast cancer with no evidence of an effect with fractionation schedule. Coexisting cardiac risk factors are common in the population.

Treatment of Glioblastoma in Older Adults.

Glioblastoma is the most common primary malignant brain tumor diagnosed in the USA and is associated with a poor prognosis. The outcomes in elderly patients (more than 65years of age) are worse when compared to those younger than age 65 at the time of diagnosis. Older patients are not always offered treatments that would otherwise be considered standard of care due to comorbidities and concerns about toxicity and tolerability. The initial European Organization for Research and Treatment of Cancer study that led to approval of temozolomide in glioblastoma excluded patients more than 70years of age. This review outlines challenges that arise in the treatment of glioblastoma in the elderly population and discusses results of recent studies that established the role of adjuvant chemotherapy in addition to radiation and surgery. There is evidence that these patients can benefit from a more aggressive and safe resection, from hypofractionated radiation treatments, and from adjuvant temozolomide.

Phase 3 Study of Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Adenocarcinoma of the Prostate

The low α/β ratio of prostate cancer (1.5-2) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (RT). Most available data of moderate hypofractionated RT have focused on low, intermediate, and/or mixed risk groups. We therefore conducted the first randomized trial of moderately hypofractionated RT in high-risk prostate cancer patients, with the hypothesis that moderately hypofractionated RT is similar in safety to conventional high-dose intensity-modulated RT at 24 months. Here, we present the primary outcome of the study: safety analysis of toxicities at 6 and 24 months post-RT. We conducted a Canadian multi-centric phase III trial of conventional vs. hypofractionated intensity-modulated radiotherapy in men with high-risk prostate cancer as per the ASTRO definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either conventional or hypofractionated RT. All patients received neo-adjuvant, concurrent, and adjuvant androgen suppression, with a median duration of 24 months. Conventional RT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The primary endpoint is to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. This study is registered on clinicaltrials.gov (NCT01444820). Of the 329 patients, 164 were randomized to hypofractionated RT and 165 to conventional RT. The median follow-up was 36 months (19-55 months). At 24 months, 8 patients in the conventional RT arm and 9 patients in the hypofractionated RT arm had grade 2 or worse gastrointestinal (GI) related adverse events (HR = 0.76; 95% CI = 0.26-2.19; P = ns). Similarly, 7 patients in the conventional RT arm and 5 patients in hypofractionated RT arm had grade 2 or worse genitourinary (GU) toxicities (HR = 0.57; 95% CI = 0.17-1.95; P = ns). Three patients in the hypofractionated RT arm and no patient in the conventional RT arm had grade 3 GI related toxicities, while one patient in hypofractionated RT group and 3 patients in conventional RT group had grade 3 GU related toxicities. There were no grade 4 toxicities in any of the groups. This is the first hypofractionated dose escalated radiotherapy study in high-risk prostate cancer patients treated with contemporary radiation techniques and androgen suppression. The results confirm our original hypothesis and indicate that moderate hypofractionated RT is equally well tolerated as conventionally fractionated radiotherapy at 2 years in high-risk prostate cancer patients.