Standard Fractionation Radiotherapy Research Articles

Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non–Small-Cell Lung Cancer

Purpose/ObjectivesAdoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection. Materials/MethodsWe evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts. ResultsFifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation ConclusionIn select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

Intracranial meningiomas: an update of the 2021 World Health Organization classifications and review of management with a focus on radiation therapy.

Meningiomas account for approximately one third of all primary intracranial tumors. Arising from the cells of the arachnoid mater, these neoplasms are found along meningeal surfaces within the calvarium and spinal canal. Many are discovered incidentally, and most are idiopathic, although risk factors associated with meningioma development include age, sex, prior radiation exposure, and familial genetic diseases. The World Health Organization grading system is based on histologic criteria, and are as follows: grade 1 meningiomas, a benign subtype; grade 2 meningiomas, which are of intermediately aggressive behavior and usually manifest histologic atypia; and grade 3, which demonstrate aggressive malignant behavior. Management is heavily dependent on tumor location, grade, and symptomatology. While many imaging-defined low grade appearing meningiomas are suitable for observation with serial imaging, others require aggressive management with surgery and adjuvant radiotherapy. For patients needing intervention, surgery is the optimal definitive approach with adjuvant radiation therapy guided by extent of resection, tumor grade, and location in addition to patient specific factors such as life expectancy. For grade 1 lesions, radiation can also be used as a monotherapy in the form of stereotactic radiosurgery or standard fractionated radiation therapy depending on tumor size, anatomic location, and proximity to dose-limiting organs at risk. Optimal management is paramount because of the generally long life-expectancy of patients with meningioma and the morbidity that can arise from tumor growth and recurrence as well as therapy itself.

Long-Term Follow-up of a Randomized Controlled Trial on Accelerated Radiation Therapy Versus Standard Fractionated Radiation Therapy for Early Glottic Cancer (JCOG0701A3)

We previously reported the primary results of JCOG0701, a randomized, multicenter, phase III, non-inferiority trial comparing accelerated fractionation (Ax) to standard fractionation (SF) for early glottic cancer (GC). In the primary results, although the similar efficacy of 3-year PFS and toxicity of Ax compared with SF was observed, the non-inferiority of Ax was not confirmed statistically. To evaluate the long-term follow-up results of JCOG0701, we conducted JCOG0701A3 as an ancillary study of JCOG0701. In JCOG0701, 370 patients were randomly assigned to receive SF of 66-70 Gy (33-35 fractions) (n=184) or Ax of 60-64.8 Gy (25-27 fractions) (n=186). The data cutoff date for this analysis was in June 2020. Overall survival, progression-free survival, and late adverse events including central nervous system ischemia (CNSI) were analyzed. With median follow-up period of 7.1 years (range: 0.1-12.4), PFS of the SF and Ax arms were 76.2% and 78.2% at 5 years and 72.7% and 74.8% at 7 years (p=0.44). OS of SF and Ax arms were 92.7% and 89.6% at 5 years and 90.8% and 86.5% at 7 years (p=0.92). Among 366 patients with a protocol treatment, the cumulative incidence of late adverse events of SF and Ax arms were 11.9% and 7.4% at 8 years (HR: 0.53, 95% CI: 0.28-1.01, p=0.06). CNSI of Grade 2 or higher was observed in 4.1% for SF arms and 1.1% for Ax arm (p=0.098). After a long-term follow-up Ax showed comparable efficacy to SF and a tendency for better safety. Ax may be suitable for early GC because of its convenience in minimizing treatment time, cost, and labor.

Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial

The low α\β ratio of 1.2 to 2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date, no phase 3 randomized clinical trial has compared moderately HF RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderate HF RT in high-risk PCa in an initially noninferiority-designed phase 3 clinical trial. From February 2012 to March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF RT. All patients received neoadjuvant, concurrent, and long-term adjuvant androgen deprivation therapy. Standard fractionation 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 included 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 coprimary endpoints were acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a noninferiority with a 5% absolute margin. Given the lower-than-expected toxicities in both arms, the noninferiority analysis was completely dropped. Of the 329 patients, 164 were randomized to the HF and 165 to the SF arms. In total, there were more grade 1 or worse acute gastrointestinal (GI) events in the HF arm, 102 versus 83 events in the HF and SF arm, respectively (P=.016). This did not remain significant at 8 weeks of follow-up. There were no differences in grade 1 or worse acute GU events in the 2 arms, 105 versus 99 events in the HF and SF arm, respectively (P=.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade 2 or worse delayed GI-related adverse events (hazard ratio, 1.32; 95% CI, 0.62-2.83; P=.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade 2 or higher delayed genitourinary (GU) toxicities (hazard ratio, 0.26; 95% CI, 0.07-0.94; P=.037). There were 3 grade 3 GI and one grade 3 GU delayed toxicities in the HF arm and 3 grade 3 GU and no grade 3 GI toxicities in the SF arm. No grade 4-toxicities were reported. This is the first study of moderate HF dose-escalated RT in exclusively high-risk patients with prostate cancer treated with long-term androgen deprivation therapy and pelvic RT. Although our data were not analyzed as a noninferiority, our results demonstrate that moderately HF RT is well-tolerated, similar to SF RT at 2 years, and could be considered an alternative to SF RT.

Early Experience of Online Adaptive Radiation Therapy for Definitive Radiation of Patients With Head and Neck Cancer

The advent of cone beam computed tomography-based online adaptive radiation therapy (oART) has dramatically reduced the barriers of adaptation. We present the first prospective oART experience data in radiation of head and neck cancers (HNC). Patients with HNC receiving definitive standard fractionation (chemo)radiation who underwent at least 1 oART session were enrolled in a prospective registry study. The frequency of adaptations was at the discretion of the treating physician. Physicians were given the option of delivering 1 of 2 plans during adaptation: the original radiation plan transposed onto the cone beam computed tomography with adapted contours (scheduled), and a new adapted plan generated from the updated contours (adapted). A paired t test was used to compare the mean doses between scheduled and adapted plans. Twenty-one patients (15 oropharynx, 4 larynx/hypopharynx, 2 other) underwent 43 adaptation sessions (median, 2). The median ART process time was 23 minutes, median physician time at the console was 27 minutes, and median patient time in the vault was 43.5 minutes. The adapted plan was chosen 93% of the time. The mean volume in each planned target volume (PTV) receiving 100% of the prescription dose for the scheduled versus adapted plan for high-risk PTVs was 87.8% versus 95% (P < .01), intermediate-risk PTVs was 87.3% versus 97.9% (P < .01), and low-risk PTVs was 94% versus 97.8% (P < .01), respectively. The mean hotspot was also lower with adaptation: 108.8% versus 106.4% (P < .01). All but 1 organ at risk (11/12) saw a decrease in their dose with the adapted plans, with the mean ipsilateral parotid (P=.013), mean larynx (P < .01), maximum point spinal cord (P < .01), and maximum point brain stem (P=.035) reaching statistical significance. Online ART is feasible for HNC, with significant improvement in target coverage and homogeneity and a modest decrease in doses to several organs at risk.

Metrics of dose to highly ventilated lung are predictive of radiation-induced pneumonitis in lung cancer patients

PurposeTo identify metrics of radiation dose delivered to highly ventilated lung that are predictive of radiation-induced pneumonitis. Methods and MaterialsA cohort of 90 patients with locally advanced non-small cell lung cancer treated with standard fractionated radiation therapy (RT) (60–66 Gy in 30–33 fractions) were evaluated. Regional lung ventilation was determined from pre-RT 4-dimensional computed tomography (4DCT) using the Jacobian determinant of a B-spline deformable image registration to estimate lung tissue expansion during respiration. Multiple voxel-wise population- and individual-based thresholds for defining high functioning lung were considered. Mean dose and volumes receiving dose ≥ 5–60 Gy were analyzed for both total lung-ITV (MLD,V5-V60) and highly ventilated functional lung-ITV (fMLD,fV5-fV60). The primary endpoint was symptomatic grade 2+ (G2+) pneumonitis. Receiver operator curve (ROC) analyses were used to identify predictors of pneumonitis. ResultsG2+ pneumonitis occurred in 22.2% of patients, with no differences between stage, smoking status, COPD, or chemo/immunotherapy use between G<2 and G2+ patients (P≥ 0.18). Highly ventilated lung was defined as voxels exceeding the population-wide median of 18% voxel-level expansion. All total and functional metrics were significantly different between patients with and without pneumonitis (P≤ 0.039). Optimal ROC points predicting pneumonitis from functional lung dose were fMLD ≤ 12.3 Gy, fV5 ≤ 54% and fV20 ≤ 19 %. Patients with fMLD ≤ 12.3 Gy had a 14% risk of developing G2+ pneumonitis whereas risk significantly increased to 35% for those with fMLD > 12.3 Gy (P = 0.035). ConclusionsDose to highly ventilated lung is associated with symptomatic pneumonitis and treatment planning strategies should focus on limiting dose to functional regions. These findings provide important metrics to be used in functional lung avoidance RT planning and designing clinical trials.

Retrospective Analysis of Clinical Outcomes of Stereotactic Body Radiation Therapy for Localized Prostate Cancer at an Asian Cancer Specialist Centre.

The current treatment options for localized prostate cancer are radical prostatectomy and external beam radiotherapy (EBRT) with stereotactic body radiation therapy (SBRT) gaining interest as a treatment option compared to standard fractionation radiation therapy. This present study is a retrospective study evaluating the correlations between the biochemical efficacy, and treatment toxicity in SBRT for localized prostate cancer. All organ-confined prostate cancer patients treated with SBRT from 2010 to 2018, at Beacon Hospital, Malaysia were included in this study. Patient demographics, dosimetric parameters, and disease information were retrospectively collected. The primary endpoint was biochemical recurrence-free survival assessed using the Phoenix definition (Nadir + 2 ng/mL). Toxicity outcomes were scored using the Radiation Therapy Oncology Group scale. Fourty-nine patients who met the inclusion criteria (5 low-, 13 intermediate- and 31 high-risk according to the D'amico Risk Classification) received SBRT. The most common dose regime was 34-35Gy in 5 fractions (n=18). Other dose regimes were 24Gy in 3 fractions and 25-33Gy in 5 fractions. Median follow-up was 45.4 months. The median pre-treatment prostate-specific antigen (PSA) was 11.22 ng/mL, which decreased to a median PSA of 0.1 ng/mL by 2 years post-treatment. Out of the 49 cases, only 1 case of biochemical recurrence occurred, yielding a 3- and 5-year overall survival of 100%, and a 3- and 5- year biochemical recurrence-free rate of 100% and 95.2%. Acute grade III urinary toxicities occurred in 1 (2%); whereas acute grade I urinary and rectal toxicities were seen in 22 (44.9%) and 7 (14.3%) patients respectively. Grade I and grade III late rectal toxicities occurred in 3 and 1 patients respectively, while 3 and 1 patient reported late grade I and III urethral stricture respectively. SBRT for clinically-localized and locally advanced prostate cancer provided promising outcomes with low toxicity and good biochemical control.

AESOP: Phase 2 Open-Label Trial of Avasopasem Manganese (GC4419) for Reduction of Esophagitis in Patients Receiving Chemoradiotherapy for Nonmetastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> National Cancer Institute (NCI) grade 3+ esophagitis has been reported in up to 20% of advanced lung cancer patients receiving standard fractionation radiotherapy with concurrent chemotherapy (Provencio 2011, Curran 2011). Avasopasem (GC4419) is an investigational selective dismutase mimetic that rapidly and selectively converts superoxide to hydrogen peroxide, interrupting the initiation of radiation-induced mucosal injury (Thompson 2010, Sonis 2021). Avasopasem demonstrated the potential to reduce severe oral mucositis due to chemoradiotherapy for head and neck cancer in a randomized phase 2 clinical trial (Anderson 2019), supporting the hypothesis that avasopasem might reduce severe radiation-induced esophagitis in patients with lung cancer. <h3>Materials/Methods</h3> In a single-arm open-label trial, patients with stage 3 or post-operative stage 2B non-small cell lung cancer (NSCLC) or limited stage small-cell lung cancer (LS-SCLC) received 90 mg avasopasem by 60-minute infusion prior to radiation therapy (1.8–2.0 Gy 5 days/week up to 60 Gy total), in combination with investigator's choice of chemotherapy other than gemcitabine. Primary objective to assess the incidence of acute (NCI ≥gr 2) radiation esophagitis, with observed incidence of grade 3–4 radiation esophagitis as a secondary endpoint. <h3>Results</h3> A total of 39 patients were enrolled and received at least 1 dose of avasopasem: median age 64 (range 38–85); 22 (56.4%) were male; 95% performance status (PS) 0 or 1. Thirty-two (82.1%) had NSCLC and 7 (17.9%) had LS-SCLC. Median duration of exposure to avasopasem was 43.0 days (range 2–54). Preliminary results with data analysis ongoing showed 14 of 29 evaluable patients (48.3%) experienced acute esophagitis at week 6 (95% confidence interval [CI], 29.5–67.5). Of these, 13 (44.8%) were grade 2 and 1 (3.4%) was grade 3; there were no grade 4 events. Adverse events (AEs, all grades) considered possibly related to avasopasem occurring in at least 15% of patients were nausea (36%), paresthesia (26%), dizziness, fatigue (21% each), and hypotension (15%). Three patients had grade 3 AEs (7 events) possible related to avasopasem (nausea, vomiting, dehydration, hypokalemia, dysphagia, muscular weakness, hypoxia). <h3>Conclusion</h3> In this phase 2 open-label study, grade 3 esophagitis was infrequent with avasopasem at an unscheduled interim analysis. The AE profile appeared consistent with expectations for standard therapy and avasopasem appeared well tolerated. Final data will be presented at the conference. This study (NCT04529850) is funded by Galera Therapeutics, Inc.

Ten-Year Follow-Up on 160 Patients Treated with Hypofractionated Prostate Salvage Radiation Therapy

<h3>Purpose/Objective(s)</h3> Patients with biochemical failure after prostatectomy are commonly treated with standard fractionation radiotherapy requiring 6.5-8 weeks of treatment. GU003 recently reported favorable short-term efficacy and acceptable toxicity using hypofractionated salvage radiotherapy after prostatectomy. However, follow-up for the study is short and questions remain regarding whether late toxicities will remain acceptable. Here, we report on long term outcomes of patients treated with a similar regimen. <h3>Materials/Methods</h3> We evaluated a consecutive cohort of patients treated from 2003-2013 with salvage RT to 65-70 Gy in 25-28 fractions using image-guided IMRT. Freedom from biochemical recurrence (FFBR), prostate cancer specific survival (PCSS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Factors associated with biochemical failure were assessed using Cox regression analysis (surgical margins, Gleason score ≥8, PSA nadir, time to detectable PSA, PSA doubling time, and presalvage PSA). Late GU toxicities were scored based on a modified LENT/RTOG grading system. <h3>Results</h3> A total of 160 patients were identified with a median follow-up of 155 months. Twenty-six patients (16.3%) received androgen deprivation therapy following surgery or concurrently with radiation and 20 patients (12.5%) had lymph nodes electively treated. FFBR was 63% at 5 years and 56% at 10 years; PCSS was 99% at 5 years and 93% at 10 years; OS was 97% at 5 years and 85% at 10 years. Factors associated with increased biochemical recurrence included negative surgical margin status and higher pre-salvage PSA (p =0.025, 0.050). Total incidence grade ≥3 late toxicities was 21.9% (n=35, 33 GU, 1 GI, 1 lymphovascular) which were observed a median of 101 months after the end of radiation. There were four late grade 4 toxicities and three observed deaths potentially associated with radiation (urothelial cancer, urosepsis related to a suprapubic catheter, and pelvic sarcoma). <h3>Conclusion</h3> Prostate cancer has a long natural history as do many late RT toxicities. This cohort of patients with >10 years follow-up treated with hypofractionated salvage RT shows long-term control comparable to that seen in other salvage RT series with long-term follow-up. Although we do not have a comparator group treated with standard fractionation, these data illustrate the importance of long-term follow-up when considering toxicity from salvage RT.

Correlation of an Electronic Geriatric Assessment With Receipt of Adjuvant Radiation and Chemotherapy in Older Adults With Head and Neck Cancer

PurposeTreatment patterns for head and neck squamous cell carcinoma (HNSCC) vary among older adults because of concerns about their health status. Geriatric assessment may guide treatment for older adults with HNSCC by assessing their health status. Methods and MaterialsWe conducted a retrospective review of adjuvant treatment received by older patients with HNSCC who completed a novel geriatric assessment, the electronic Rapid Fitness Assessment, before treatment. The electronic Rapid Fitness Assessment yields an accumulated geriatric deficits (AGD) score. Higher AGD score indicates greater frailty. Comparators were age and performance status. The Wilcoxon rank sum test compared differences between those who did and did not receive adjuvant radiation therapy and chemotherapy. ResultsThe cohort included 73 patients, of whom 56 (77%) had oral cavity cancer. The most common geriatric deficits were major distress, social activity limitation, depression, and impaired activities of daily living. AGD score, age, and performance status were not associated with receipt of adjuvant radiation. Patients who received adjuvant chemotherapy had a significantly lower median AGD score than those who did not (3 vs 6; P = .044), but there was no association with age and performance status. Of the 17 patients with newly diagnosed disease and either positive margins or extranodal extension, only 9 received adjuvant radiation and only 3 received systemic therapy. Most often, systemic therapy was omitted because of patient preference or comorbidities and poor performance status. There was a nonstatistically significant lower AGD score between patients who did and did not receive standard fractionated radiation therapy (median, 4 vs 6.5; P = .13). ConclusionsReceipt of adjuvant chemotherapy was associated with frailty. Rates of chemotherapy utilization were very low, indicating the need for novel strategies to mitigate the toxicity burden in this patient population. Receipt of adjuvant radiation therapy was not associated with frailty; however, there was a trend toward lower frailty among those who did receive radiation therapy.

The Role of Thoracic Radiation Therapy Dosing in the Treatment of Limited-Stage Small Cell Lung Cancer: A Study Based on the National Cancer Database

PurposeSmall cell lung cancer (SCLC) is a highly fatal disease, but its treatment has remained relatively unchanged for decades. Randomized clinical trials evaluating radiation therapy (RT) dosing and fractionation have yielded mixed results on overall survival (OS). Methods and MaterialsWe identified 2261 patients with limited-stage (LS) SCLC undergoing definitive RT at 1.5, 1.8, and 2.0 Gy dose per fraction, concurrently with chemotherapy, between 2004 and 2015 within the National Cancer Database. Overall survival (OS) was evaluated using the Kaplan-Meier method, and Cox proportional hazards regression was used to investigate whether there was any survival difference among patients who received hyperfractionated, twice-daily RT at 1.5 Gy per fraction (HF1.5) and once-daily, standard fractionation RT at 1.8 Gy (SF1.8) or 2.0 Gy (SF2.0) per fraction. Subgroup analyses by age, sex, race, time to RT, facility type, and Charlson comorbidity index were also performed. ResultsAll stage median OS rates for HF1.5, SF1.8, and SF2.0 Gy groups were 21.6, 18.9, and 19.4 months, respectively (log-rank P = .0079). Multivariate analyses adjusting for demographic factors, socioeconomic status, tumor characteristics, and year of diagnosis showed SF1.8 (hazard ratio [HR] = 1.30, 1.03-1.63) and SF2.0 (HR = 1.20, 1.00-1.45) was associated with worse 1-year survival compared with HF1.5. This association was more evident in stage IIb-stage III than stage I to stage IIa patients. Propensity score–weighted analysis showed similar results. Stratified analyses showed the significant associations were confined to male or black patients, those aged >65 years, with 1 comorbidity, who had waited >60 days to start RT or were treated at an academic medical center. ConclusionsAnalyses of real-world treatment outcome data showed that receiving hyperfractionated, twice-daily RT was associated with improved survival among patients with LS-SCLC compared with standard, once-daily fractionation regimens at 1 year after diagnosis, particularly for subsets of patients. Some associations retained statistical significance 3 years postdiagnosis.

Intensification of radiation therapy for&#x0D; localized breast cancer in the settings of the&#x0D; COVID-19 pandemic: A literature review

Relevance: Since 2004, breast cancer steadily ranks first in the&#x0D; structure of the incidence of malignant neoplasms in the Republic of&#x0D; Kazakhstan in both sexes. In 2020, its share was 14.5% (vs. 15.2% in&#x0D; 2019). Breast cancer also constantly ranks first in the structure of female cancer incidence, with 44.3‰ in 2020 (vs. 51.6‰in 2019).&#x0D; In the early 1980s, radiation therapy was a standard specialized&#x0D; treatment for breast cancer. The current realities of the COVID-19&#x0D; pandemic require a reorganization of healthcare facilities to determine the priorities. It is also important to balance the economic and&#x0D; clinical efficacy of radiotherapy methods applied.&#x0D; The study aimed to analyze the results of large randomized trials and compare breast cancer outcomes after hypofractionated and standard fractionation radiation treatment.&#x0D; Methods: We reviewed the results of large randomized trials&#x0D; of hypofractionated radiation therapy, emphasizing adequate&#x0D; patient selection according to the American Society of Therapeutic Radiology and Oncology (ASTRO) guidelines. Radiobiological&#x0D; aspects of hypofractionation were considered due to its implementation in clinical practice. The research materials were obtained from the “PubMed” database of evidence-based medicine&#x0D; by the keywords “radiotherapy,” “breast cancer,” “hypofractionation dose” for the period 2000-2021. Large randomized trials&#x0D; involving patients of any age diagnosed with stages T1-3, N0-1&#x0D; breast cancer, who underwent beam therapy in standard or hypofractionated mode, met the criteria for inclusion in this study.&#x0D; Results: According to the results of large randomized trials,&#x0D; the hypofractionated regimen is similar to the standard regimen in terms of late effects on normal tissues and ensures good&#x0D; control over the oncological process.&#x0D; Conclusions: Hypofractionation has proven effectiveness&#x0D; and safety and has lower late and/or acute radiation toxicity&#x0D; when treating early breast cancer. Hypofractionation can become a new standard of radiation therapy at early stages after&#x0D; breast-conserving surgery.

Intensification of radiation therapy for localized breast cancer in the settings of the COVID-19 pandemic: A literature review

Relevance: Since 2004, breast cancer steadily ranks first in the structure of the incidence of malignant neoplasms in the Republic of Kazakhstan in both sexes. In 2020, its share was 14.5% (vs. 15.2% in 2019). Breast cancer also constantly ranks first in the structure of female cancer incidence, with 44.3 0⁄0000 in 2020 (vs. 51.6 0⁄0000 in 2019). In the early 1980s, radiation&#x0D; therapy was a standard specialized treatment for breast cancer. The current realities of the COVID-19 pandemic require a reorganization of healthcare facilities to determine the priorities. It is also important to balance the economic and clinical efficacy of radiotherapy methods applied.&#x0D; The study aimed to analyze the results of large randomized trials and compare breast cancer outcomes after hypofractionated and standard fractionation radiation treatment.&#x0D; Methods: We reviewed the results of large randomized trials of hypofractionated radiation therapy, emphasizing good patient selection according to the American Society of Therapeutic Radiology and Oncology (ASTRO) guidelines. Radiobiological aspects of hypofractionation were considered due to its implementation in clinical practice. The research materials were obtained from the “PubMed” database of evidence-based medicine by the keywords “radiotherapy,” “breast cancer,” “hypofractionation dose” for the period of 2000-2021. Large randomized trials involving patients of any age diagnosed with stages T1-3, N0-1 breast cancer, who underwent beam therapy in standard or hypofractionated mode, met the criteria for inclusion in this study.&#x0D; Results: According to the results of large randomized trials, the hypofractionated regimen is similar to the standard regimen in terms of late effects on normal tissues and ensures reasonable control over the oncological process.&#x0D; Conclusions: Hypofractionation has proven effectiveness and safety and lower late and acute radiation toxicity when treating early breast cancer. Hypofractionation can become a new standard of radiation therapy at early stages after breast-conserving surgery.

A Pilot Study to Quantify Breast Lymphedema for Patients Undergoing Breast Conserving Therapy (BCT) for Breast Cancer

<h3>Purpose/Objective(s)</h3> Upper extremity lymphedema after axillary lymph node dissection and radiation for breast cancer has been well described and studied. As modern treatment techniques have reduced the incidence of arm lymphedema, breast lymphedema has emerged as a common result of BCT and is associated with poor wound healing, infection and impact on quality of life. Because there is no established tool for its evaluation and quantification, we explored the feasibility of using ultrasound to measure breast lymphedema objectively. We evaluated whether this measure correlated with clinical assessment, treatment factors, and patient-reported outcomes. <h3>Materials/Methods</h3> We enrolled 30 women with malignant breast cancer treated with breast conserving surgery, sentinel lymph node biopsy, and breast radiation. Another 10 women with benign disease who had not undergone BCT were sampled as controls. Ultrasound measurements of dermal thickness were performed on the treated breast and untreated breast at the 6:00 position. Post-treatment assessments included physical exam and quality of life DASH questionnaire. We quantified breast lymphedema as the dermal thickness of the affected breast minus the dermal thickness of the unaffected breast. Breast lymphedema was considered present if dermal thickness difference was above the highest-observed value in the benign patients. <h3>Results</h3> Mean age (± SD) was SD 59 ± 13 in the malignant group and 46.4 ± 17 in the benign group and groups were similar with regard to body mass index. Mean dermal thickness difference was higher in the malignant group compared with the benign group (1.03 mm and 0 mm, respectively). Seventy percent of patients in the malignant group met our definition of breast lymphedema (n = 21) and were more likely to report impact on quality of life pertaining to sexual activity (24% vs 11%), breast sensation (52% vs 16%), sleep quality (33% vs 21%) and confidence (24% vs 5%) than patients without breast lymphedema. Extent of axillary surgery was associated with a 1.29 mm increase in difference in dermal thickness for patients with > = 4 nodes removed (95% CI: -0.22, 2.80). The volume of breast tissue radiated was also positively associated, with every 100cc increase in breast volume radiated associated with a 0.17mm greater dermal thickness difference (95% CI: 0.04, 0.30mm). However, there was no association with percent of breast tissue receiving > 105% of prescribed dose (95% CI: -0.07, 0.01), hypofractionation vs. standard fractionation (95% CI: -1.2, 0.68) or total radiation dose (95% CI: -0.5, 1.2). <h3>Conclusion</h3> Breast lymphedema is an impactful sequela of breast cancer treatment but remains understudied with no standard measurement tools. Our pilot study demonstrates that ultrasound is a promising tool for the characterization of breast lymphedema and may improve our understanding of patient and modifiable treatment risk factors.

Five Year Results of Short Course Complete Androgen Blockade With Abiraterone Acetate and LHRH Agonist for Unfavorable Intermediate and Favorable High Risk Prostate Cancer

Purpose/Objective(s)Androgen deprivation therapy (ADT) and radiotherapy (RT) are synergistic, and the combination results in improved survival outcomes for aggressive prostate cancers. However, long-term ADT carries substantial burden of toxicity and morbidity. We hypothesized that a combination of definitive prostate RT and short-term complete androgen blockade (CAB) in men with unfavorable intermediate or favorable high-risk localized PC would provide excellent biochemical control and allow high rates of testosterone recovery. This combination would allow an escalation of therapy for unfavorable intermediate risk and de-escalation for favorable high-risk patients. We tested this hypothesis in a prospective trial of neoadjuvant/concurrent/adjuvant abiraterone acetate, prednisone, and LHRH agonist given for 6 months in conjunction with definitive prostate external beam RT. We now report the mature results of this trial.Materials/Methods37 men were enrolled in an IRB-approved NCT-registered prospective multi-center single arm investigator-initiated trial between January 2014 and August 2016. Eligibility required unfavorable intermediate risk of low volume high risk (NCCN) prostate cancer. All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior to standard fractionation RT to prostate/seminal vesicles +/- pelvis. Endpoints included PSA and testosterone (T) kinetics, biochemical progression-free survival (PFS), metastasis-free survival (MFS), overall survival (OS), and patient-reported quality-of-life.ResultsEnrolled patients were low volume (T1-2 disease and PSAs < 20 ng/ml), with Grade Group 1 (11%), 2 (11%), 3 (35%), 4 (27%), and 5 (16%); 43% were high-risk. The median follow-up time among all 37 surviving patients is 58months (range 24-65). Treatment was well tolerated and has been reported previously. In the entire cohort, 5-year BPFS was 92% (95% CI 72-98%). 32 out of 37 men recovered T to at least 150 ng/dl; the median time to T recovery was 9.2 mo (95% CI: 9.0-12.2). In men with T recovery, the 5-year BPFS was also 92% (95% CI: 71-98%). Hormonal/sexual function declined at six months but had improved by 24 mo and remained stable thereafter.ConclusionFor select men with aggressive prostate cancer, short course CAB with abiraterone acetate plus prednisone in combination with definitive prostate RT allows rapid T recovery and can provide excellent biochemical control up to 5 years. Short-course CAB is feasible for favorable high risk prostate cancer and may support optimization of patient quality of life. Prospective randomized trials should be considered. Androgen deprivation therapy (ADT) and radiotherapy (RT) are synergistic, and the combination results in improved survival outcomes for aggressive prostate cancers. However, long-term ADT carries substantial burden of toxicity and morbidity. We hypothesized that a combination of definitive prostate RT and short-term complete androgen blockade (CAB) in men with unfavorable intermediate or favorable high-risk localized PC would provide excellent biochemical control and allow high rates of testosterone recovery. This combination would allow an escalation of therapy for unfavorable intermediate risk and de-escalation for favorable high-risk patients. We tested this hypothesis in a prospective trial of neoadjuvant/concurrent/adjuvant abiraterone acetate, prednisone, and LHRH agonist given for 6 months in conjunction with definitive prostate external beam RT. We now report the mature results of this trial. 37 men were enrolled in an IRB-approved NCT-registered prospective multi-center single arm investigator-initiated trial between January 2014 and August 2016. Eligibility required unfavorable intermediate risk of low volume high risk (NCCN) prostate cancer. All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior to standard fractionation RT to prostate/seminal vesicles +/- pelvis. Endpoints included PSA and testosterone (T) kinetics, biochemical progression-free survival (PFS), metastasis-free survival (MFS), overall survival (OS), and patient-reported quality-of-life. Enrolled patients were low volume (T1-2 disease and PSAs < 20 ng/ml), with Grade Group 1 (11%), 2 (11%), 3 (35%), 4 (27%), and 5 (16%); 43% were high-risk. The median follow-up time among all 37 surviving patients is 58months (range 24-65). Treatment was well tolerated and has been reported previously. In the entire cohort, 5-year BPFS was 92% (95% CI 72-98%). 32 out of 37 men recovered T to at least 150 ng/dl; the median time to T recovery was 9.2 mo (95% CI: 9.0-12.2). In men with T recovery, the 5-year BPFS was also 92% (95% CI: 71-98%). Hormonal/sexual function declined at six months but had improved by 24 mo and remained stable thereafter. For select men with aggressive prostate cancer, short course CAB with abiraterone acetate plus prednisone in combination with definitive prostate RT allows rapid T recovery and can provide excellent biochemical control up to 5 years. Short-course CAB is feasible for favorable high risk prostate cancer and may support optimization of patient quality of life. Prospective randomized trials should be considered.

Hypofractionated radiation therapy with temozolomide versus standard chemoradiation in patients with glioblastoma multiforme (GBM): A prospective, single institution experience.

the study aimed to determine whether hypofractionated radiotherapy (HFRT) with simultaneous and adjuvant temozolomide (TMZ) was feasible and could provide adequate disease control in primary GBM patients with poor prognostic factors including large tumor size, poor performance status, unresectable or multifocal lesions, poor imaging and inflammatory indices. A total of 93 patients with glioblastoma multiforme were collected and distributed randomly as 1:1.7 of cases to controls; cases or arm (I) received HFRT with 45 Gy in 15 fractions over 3 weeks concurrently with TMZ. Controls or arm (II) received standard conventional fractionation radiotherapy of 60 Gy in 30 fractions over 6 weeks concurrently with TMZ. 35 patients were recruited in arm I while 58 patients in arm II with significant difference in site of GBM, pattern of enhancement, type of surgery, and neutrophil to lymphocyte ratio, while no significant differences in tumor size, focality, responses, progression free survival, and overall survival (OS), only the type of surgery was an independent predictor for OS, no significant difference in the type and degree of toxicity between both arms. Our results showed that HFRT with concurrent TMZ is a feasible therapeutic approach in patients with GBM, especially those with poor prognostic factors, assuring high treatment compliance and low toxicity rates. Dose escalation and reduction in overall treatment time are clear advantages of HFRT, while at least the same survival rates as conventional fractionated RT are maintained.

Long-term outcome comparison for standard fractionation (>59 Gy) versus hyperfractionated (>45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer.

Concurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses. Data were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups. From 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6-105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups. The present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.

Outcomes in Elderly Patients with Glioblastoma Treated with Standard Fractionated Radiation Therapy

Outcomes in Elderly Patients with Glioblastoma Treated with Standard Fractionated Radiation Therapy

Effect of Radiotherapy Variables on Circulating Effectors of Immune Response and Local Microbiome

Effective radiation (RT) induced immunogenicity requires sufficient numbers of effector and memory T-cells in order to generate anti-tumor immune response. Standard RT regimens, with daily exposure of active hematopoietic tissue and circulating lymphocytes over 4-8 weeks result in treatment-induced lymphopenia. Improvements in RT technology allow for hypofractionated regimens, potentially mitigating the risk of lymphopenia. In this study, we hypothesize that differences in RT fractionation (short versus protracted) and field size (whole breast vs partial breast) may result in different effects on circulating immune mediators. To test this hypothesis, we are prospectively studying patients with breast or prostate cancer undergoing standard protracted vs short-course hypofractionated RT. This is an ongoing prospective non-randomized study assessing 4 distinct cohorts of cancer patients: localized prostate cancer undergoing standard fractionation RT to at least 70 Gy (cohort 1A) vs stereotactic body RT in 5 fxs (cohort 1B); or localized breast cancer patients undergoing standard fractionation RT (cohort 2A) vs partial breast RT in 5 fxs (cohort 2B). Blood samples are collected at baseline, at midpoint during RT, at completion of treatment and at 3-6 months after completion of RT. Lymphocyte counts are obtained and characterization of T-cell subsets is performed using multi-parameter flow cytometry. Inflammatory cytokines in the plasma are measured using bead-based multi-analyte immunoassay. The study has thus far accrued 33/60 planned patients, 13 of whom have completed all 4 blood draws (Cohorts 1A n=3, 1B n=4, 2A n=0, 2B n=6). A significant (P=0.023) decline in absolute lymphocyte count (ALC) for protracted RT patients (n=3) was detected, which persists at 3 month follow up (mean decline 0.93, SD 0.25), with both CD4 and CD8 populations impacted. Conversely, patients undergoing short course radiation (n=10) do not have depletion of ALC, with 8/10 patients maintaining stable ALC during RT. A more detailed characterization of immune subsets, including NK cells, dendritic cells and myeloid cells is ongoing, as well as analysis of inflammatory cytokines. An increase of IL-2 was noted during protracted, but not short, RT in one patient; additional datasets will be acquired. Elucidating the impact of different regimens of RT on circulating immune cells provides valuable information on how RT can best be harnessed to potentiate its immunogenic effects. These preliminary results confirm that shorter radiation courses result in less, or no lymphopenia, whereas protracted radiation courses result in persistent lymphopenia, sustained 3 months after RT is completed. Variables of RT techniques such as fractionation and field size likely impact the availability of key effectors of immune rejection, and warrant further ongoing study.

Initial toxicity, quality-of-life outcomes, and dosimetric impact in a randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer

PurposeRandomized evidence for extreme hypofractionation in prostate cancer is lacking. We aimed to identify differences in toxicity and quality-of-life outcomes between standard fractionation and extreme hypofractionated radiation in a phase 3 randomized trial. Methods and materialsWe analyzed the results of the first 75 patients in our phase 3 trial, comparing 38 Gy relative biologic effectiveness (RBE) in 5 fractions (n = 46) versus 79.2 Gy RBE in 44 fractions (n = 29). Patients received proton radiation using fiducials and daily image guidance. We evaluated American Urological Association Symptom Index (AUASI), adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains. The primary endpoint of this interim analysis was the cumulative incidence of grade 2 (G2) or higher AEs. The randomized patient allocation scheme was a 2:1 ratio favoring the 38 Gy RBE arm. ResultsThe median follow-up was 36 months; 30% of patients reached 48-month follow-up. AUASI scores differed <5 points (4.4 vs 8.6; P = .002) at 1 year, favoring the 79.2 Gy arm. Differences in AUASI were not significant at ≥18 months. EPIC urinary symptoms favored the 79.2 Gy arm at 1 year (92.3 vs 84.5; P = .009) and 18 months (92.3 vs 85.3; P = .03); bother scores were not significant at other time points. Cumulative ≥G2 genitourinary toxicity was similar between the 79.2 Gy and 38 Gy arms (34.5% vs 30.4%; P = .80). We found no differences in the EPIC domains of bowel symptoms, sexual symptoms, or bowel ≥G2 toxicities. Bladder V80 (79.2 Gy arm; P = .04) and V39 (38 Gy arm; P = .05) were predictive for cumulative G2 genitourinary AEs. ConclusionsLow AE rates were seen in both study arms. Early temporary differences in genitourinary scores disappeared over time. Bladder constraints were associated with genitourinary AEs.