Fractionation Regimens Research Articles

Hypofractionated Versus Conventional Fractionated Radiotherapy for Reconstructed Breast Cancer: Toxicity Analysis

This study was aim to evaluate whether hypofractionated adjuvant radiotherapy (RT) increased breast-related complication(s) compared to conventional RT in reconstructed breast cancer patients. This study included 397 patients with breast cancer who underwent breast reconstruction following total mastectomy (TM) or breast-conserving surgery (BCS) between 2009 and 2019 in two institutions. All patients were treated with adjuvant radiotherapy via either hypofractionated or conventional fractionated regimen. We defined major breast complication as a breast-related toxic event requiring re-operation or re-hospitalization during follow-up period after RT. The median follow-up was 34.6 months (range, 3.6-116.9 months). Among 397 patients, 162 patients had conventional fractionated RT and 235 patients received hypofractionated RT. The 1-year and 2-year actuarial rate of any breast-related complications were 22.2% and 30.5%, and those of major breast-related complications were 7.9%, 10.2%, respectively. There was no significant difference in any and major breast-related complications between two fractionation regimens (P = 0.087 for any and P = 0.528 for major breast-related complication). In the subgroup analysis of patients with TM, hypofractionated RT showed similar breast-related complications compared to conventional fractionated RT. Major breast complications occurred 47 cases; 20 cases of wound infection, 10 wound dehiscence, 7 fat necrosis, 4 implant leakage, 3 flap contracture, 1 mastectomy skin flap necrosis, 1 seroma and 1 hematoma. In multivariate analysis, hypofractionated RT and delayed reconstruction were statistically significant factors for lower incidence of any breast complications. The factor adversely affecting major breast complications was implant reconstruction. Among patients with TM, implant reconstruction and age over 45 were associated with higher risk of major breast complications. Hypofractionated RT may be used comparably with conventional fractionated RT in terms of breast-related complications in reconstructed breast cancer patients.

Overall Survival of Patients with Early-Stage Non-Small Cell Lung Cancer Treated Daily Versus Non-Daily with Lung Stereotactic Body Radiation Therapy

Data is conflicting with regard to the influence of consecutive (daily) treatment on toxicity and even local control in patients with non-small cell lung cancer (NSCLC) treated with lung stereotactic body radiation therapy (SBRT). Small retrospective studies suggest worse toxicity and local control with daily treatment while others have found no difference in outcomes. Large national databases may have sufficient statistical power to discern differences in survival outcomes between these two treatment regimens. We used the National Cancer Database (NCDB) to identify patients with stage I or II NSCLC treated with primary radiation therapy. We included only patients treated in 3-5 fractions with a biologically effective dose (BED) of ≥ 100 Gy. Daily treatment was considered to be treatment within 6 or 7 days for 4- and 5-fraction regimens, respectively, to account for a potential weekend treatment break. Daily treatment was considered to be treatment within 3 days for 3-fraction regimens. We used 1:1 nearest neighbor propensity score matching (caliper 0.1) to balance daily and non-daily cohorts on the basis of age, race, sex, treatment facility type, education, income, insurance status, county population, distance from treatment center, Charlson comorbidity index, tumor laterality, T-stage, histology, radiation dose, and year of diagnosis. Cox regression and Kaplan-Meier analysis were used to assess the association of daily treatment with overall survival. We identified 40,161 patients, 11,168 (27.8%) of which were treated with daily treatments. Daily treatment was associated with a higher proportion of Caucasians (90.6% vs 88.7%, p < 0.001), Charlson comorbidity index of 0-2 (95% vs 93.1%; p < 0.001), treatment at an academic medical center (41.9% vs 39.1%; p < 0.001), and increased distance to treatment facility (12.6 vs 10.8 miles; p < 0.001). There were no significant differences in age or sex. After propensity-score matching, there were 7176, 6402, and 4176 patients treated with 5, 4, and 3 fraction regimens, respectively. There were no significant differences in any of the variables. For 5-fraction regimens, there was no statistically significant difference in overall survival with non-daily vs daily treatment (HR = 1.06; 95% CI 1.00 – 1.13). Non-daily treatment was associated with improved overall survival for 4-fraction (HR = 0.93; 95% CI 0.88 – 0.995; p = 0.033) and 3-fraction (HR = 0.91; 95% CI 0.85 – 0.98; p = 0.018) regimens. We found improved overall survival in patients treated with non-daily fractions when treated with 3- or 4-fraction regimes. We found no significant difference in overall survival in patients treated with 5-fraction regimens. Altering fractionation scheme may be a simple means of improving outcomes in lung SBRT. More data is warranted on the effects of altering fractionation on tumor control outcomes, and these data should be considered to be validated in the context of a prospective randomized trial.

Patient Reported Pain Improvement following Palliative Radiotherapy and Immune Checkpoint Blockade

An increasing number of patients with metastatic cancer are being treated with combinations of palliative radiotherapy (RT) and immune checkpoint blockade (ICB) in an attempt to achieve disease control and alleviate symptoms. Patient reported outcomes measures (PROM) are increasingly used to evaluate treatment effectiveness but there are few data in the metastatic setting that evaluate impacts of combined RT/ICB on PROM. We performed a retrospective chart review of patients treated with palliative RT and ICB at 5 affiliated institutions between 2015-2020 who completed PROM before and between 5 and 90 days after RT. Patient and treatment data were abstracted from the electronic medical record. PROM consisted of questions drawn from the MD Anderson Spine Index Score (MDASI) and Patient Reported Outcome Measurement Information System Global Health (PROMIS). We focused specifically on the patient reported “pain over the last week” question (rated 1-10) for this analysis. Associations between patient reported pain improvement and timing of ICB were determined using a non-parametric Wilcoxon test and Fisher’s exact test. We identified 23 patients who received 26 courses of palliative radiation. Seven patients had lung cancer, 6 had genitourinary cancers, 2 had head and neck cancer, 2 had breast cancer and 6 had other cancers. The most common indication for radiation was pain in 18 instances. Sites irradiated included bone (n = 17), spine (n = 3), WBRT (n = 2), lung and regional lymph nodes (n = 2) and multiple sites (n = 2). The most common fractionation regimens were 3Gyx10 (n = 10), 4Gyx5 (n = 6), 8Gyx1 (n = 7) and other (n = 3). Types of ICB administered were PD-1 inhibitors (n = 12) and PD-L1 inhibitors (n = 11). ICB was administered within 30 days of RT in 15 cases (63%). Post-treatment PROM were collected a median of 30 days following the last fraction of radiotherapy (IQR 26-34). In 15 out of 26 instances (58%) there was improvement in pain scores (median improvement 3, IQR 1-7). Improvement in pain score was associated with receipt of ICB in the interval between RT and post treatment PROM (p = 0.03). Specifically, 67% (n = 10) of patients who received ICB after RT and before PROM reported improvement in pain, as compared to 17% (n = 2) who did not (p = 0.02). In this retrospective review, the majority of patients treated with palliative RT and ICB had improvement in their pain scores over the last week and the receipt of ICB after RT and before PROM was associated with a greater likelihood of reported pain improvement. Although our study is limited by size and potential treatment bias, these findings should prompt further investigation as to potential synergies between ICB and pain relief provided by palliative radiotherapy.

A Prospective Analysis of Quality of Life in Patients Undergoing Whole Breast Irradiation

The impact of Whole Breast Irradiation (WBI) on Quality of Life (QoL) outcomes is unclear, especially in developing countries, therefore a prospective, observational, cohort study was conducted to gain insight into this aspect of patient care. 74 women with stage I-III breast cancer and treated with breast-conserving surgery followed by adjuvant systemic therapy, were prospectively enrolled in this study, after ethics committee approval. CT based target delineation was performed according to RTOG guidelines. The entire breast comprised the PTV, which was prescribed either 46–50 Gy in 23-25 fractions or 40–42.5Gy in 15-16 fractions, as per physician preference. All patients were treated with Forward-Optimized IMRT, following which they received a boost to the lumpectomy cavity (10 Gy in 4 fractions). QoL assessment was performed using the self-administered FACT-B questionnaire (in English or patient's native language). All FACT-B subscales [Physical (PWB), Emotional (EWB), Social (SWB) and Functional (FWB) well-being, as well as Breast Cancer-Specific Subscale (BCSS)] were assessed. The assessments were performed before starting radiotherapy, at the end of every week during radiotherapy, and at 3 and 6 months after radiotherapy. Repeated measures ANOVA was performed to determine any statistically significant differences throughout radiotherapy delivery. A comparison between baseline and every time-point henceforth was performed using the paired t-test. For the entire cohort and across all subscales, scores at 3 and 6 months were higher compared to baseline scores (p < 0.001 for all comparisons). During radiotherapy delivery, PWB, FWB and BCSS scores increased during the first week of treatment, followed by a gradual decline towards end-of-treatment, whereas SWB and EWB gradually improved (p < 0.001 for all comparisons). FACT-B score improved for first 2 weeks followed by a gradual decline towards end-of-treatment. There is a significant QoL reduction in all patients undergoing adjuvant WBI irrespective of fractionation regimen. However, QoL returned to baseline after completion of WBI.Abstract 2498; TableMean scores with standard deviations for all assessed QoL subscales. (*Week 5 & 6 assessment was performed for patients undergoing conventionally fractionated WBI)SubscalesBaselineWk 1Wk 2Wk 3Wk 4Wk 5 *Wk 6 *3 mo.6 mo.PWB9.5 ± 1.015.3 ± 2.814.2 ± 3.212.1 ± 3.49.6 ± 3.17.1 ± 3.66.1 ± 3.321.0 ± 2.915.1 ± 3.7SWB19.3 ± 1.420.8 ± 5.221.3 ± 5.122.2 ± 4.822.7 ± 4.922.8 ± 4.923.0 ± 4.825.7 ± 2.725.6 ± 3.9FWB12.5 ± 1.015 ± 5.314.1 ± 5.313.5 ± 5.512.5 ± 1.010.7 ± 5.49.8 ± 5.320.8 ± 4.517.0 ± 4.6EWB15 ± 2.815.1 ± 2.315.2 ± 2.415.4 ± 2.615.4 ± 4.815.6 ± 4.616.0 ± 4.518.7 ± 4.218.7 ± 4.1BCSS10 ± 1.421.2 ± 2.818.6 ± 3.315.6 ± 3.912.8 ± 3.910.6 ± 3.78.9 ± 3.724.4 ± 2.818.2 ± 4.8FACT-B66.4 ± 3.787.4 ± 11.383.4 ± 11.378.6 ± 12.372.5 ± 14.766.8 ± 14.663.8 ± 14.1110.5 ± 10.494.4 ± 15.4 Open table in a new tab

Radiotherapy for unresectable locally advanced non-small cell lung cancer: a narrative review of the current landscape and future prospects in the era of immunotherapy.

Significant recent advances have occurred in the use of radiation therapy for locally advanced non-small cell lung cancer (LA-NSCLC). In fact, the past few decades have seen both therapeutic gains and setbacks in the evolution of radiotherapy for LA-NSCLC. The PACIFIC trial has heralded a new era of immunotherapy and has raised important questions for future study, such as the future directions of radiation therapy for LA-NSCLC in the era of immunotherapy. Modern radiotherapy techniques such as three-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) provide opportunities for improved target conformity and reduced normal-tissue exposure. However, the low-dose radiation volume brought by IMRT and its effects on the immune system deserve particular attention when combing radiotherapy and immunotherapy. Particle radiotherapy offers dosimetric advantages and exhibits great immunoregulatory potential. With the ongoing improvement in particle radiotherapy techniques and knowledge, the combination of immunotherapy and particle radiotherapy has tremendous potential to improve treatment outcomes. Of particular importance are questions on the optimal radiation schedule in the settings of radio-immunotherapy. Strategies for the reduction of the irradiated field such as involved-field irradiation (IFI) and omission of clinical target volume (CTV) hold promise for better preservation of immune function while not compromising locoregional and distant control. In addition, different dose-fractionation regimens can have diverse effects on the immune system. Thus, prospective trials are urgently needed to establish the optimal dose fractionation regimen. Moreover, personalized radiotherapy which allows the tailoring of radiation dose to each individual’s genetic background and immune state is of critical importance in maximizing the benefit of radiation to patients with LA-NSCLC.

Hypofractionated radiation therapy comparing a standard radiotherapy schedule (over 3\xa0weeks) with a novel 1-week schedule in adjuvant breast cancer: an open-label randomized controlled study (HYPORT-Adjuvant)\u2014study protocol for a multicentre, randomized phase III trial

BackgroundHypofractionated radiotherapy is the current standard for adjuvant radiotherapy across many centres. Further hypofractionation may be possible but remains to be investigated in non-Caucasian populations with more advanced disease, with a higher proportion of patients requiring mastectomy as well as tumour bed boost. We are reporting the design of randomized controlled trial testing the hypothesis that a 1-week (5 fractions) regimen of radiotherapy will be non-inferior to a standard 3-week (15 fractions) schedule.MethodsWe describe a multicentre, randomized controlled trial recruiting patients at large academic centres across India. Patients without distant metastases who merit adjuvant radiotherapy will be eligible for inclusion in the study. Patients in the control arm will receive adjuvant radiotherapy to the breast or chest wall (with/without regional nodes) to a dose of 40 Gy/15 fractions/3 weeks, while those in the experimental arm will receive a dose of 26 Gy/5 fractions/1 week (to the same volume). The use of a simultaneous integrated boost (dose of 8 Gy and 6 Gy, respectively) is allowed in patients who have undergone breast conservation. A sample size of 2100 patients provides an 80% power to detect a non-inferiority of 3% in the 5-year locoregional recurrence rate with a one-sided type I error of 2.5%, assuming that the locoregional recurrence rate in the control arm is 5% at 5 years (corresponding to a hazard ratio of 1.63). Patients will be recruited over a period of 5 years and followed up for a further 5 years thereafter.DiscussionIf a five-fraction regimen of breast cancer is proven to be non-inferior, this will result in a significant improvement in the access to radiotherapy, as well as reduced costs of treatment. The trial gives an opportunity to standardize and quality-assure radiotherapy practices across the nation at the same time. Along with the results of the FAST-Forward trial, the safety of this intervention in advanced node-positive disease requiring regional nodal radiation will be established.Trial registrationThe trial has been registered at the Clinical Trial Registry of India (CTRI) vide registration number: CTRI/2018/12/016816 (December 31, 2018) as well as the ClinicalTrial.gov website at NCT03788213 (December 28, 2018).

A systematic review and practical considerations of stereotactic body radiotherapy in the treatment of head and neck cancer.

Stereotactic radiotherapy (SBRT) is gaining popularity although its use in head and neck cancer (HNC) is not well defined. The primary objective was to review the published evidence regarding the use of stereotactic radiotherapy in HNC. A literature search was performed by using MEDLINE and EMBASE databases for eligible studies from 2000 to 2019 and 26 relevant studies were identified. Literature demonstrates a heterogeneous use of this technique with regards to patient population, primary or salvage treatment, dose fractionation regimens, outcomes and follow-up protocols. Carotid blow out syndrome is a risk as with other forms of reirradiation but alternative treatment regimens may reduce this risk. At present there is a lack of evidence regarding SBRT as a primary treatment option for HNC and definitive answers regarding efficacy and tolerability cannot be provided but there is growing evidence that SBRT reirradiation regimens are safe and effective. In lieu of evidence from large Phase III trials, we define appropriate organ at risk constraints and prescription doses, with accurate plan summation approaches. Prospective randomised trials are warranted to validate improved treatment outcomes and acceptable treatment morbidity. This article provides a comprehensive review of evidence of use of stereotactic radiotherapy in HNC site (either as a primary treatment or as reirradiation). We also provide an evidence-based approach to the implementation and practical consideration of stereotactic radiotherapy in HNC.

Effect of reoxygenation on hypofractionated radiotherapy of prostate cancer.

To assess the role of reoxygenation of hypoxic tumor cells in hypofractionated radiotherapy of prostate cancer. The considered radiobiological model is based on the assumption of two populations (compartments) of cells: oxygenated (aerobic) cells and hypoxic cells. After each fraction of radiation, some of the hypoxic cells reoxygenate while a fraction of initially aerobic cells becomes hypoxic. The kinetics of this process between successive treatments is described by coupled, first-order differential equations. To determine the effect of reoxygenation on cell kill in the treatment target, we utilize the linear-quadratic (LQ) model assuming different radiosensitivities for the aerobic and hypoxic cells. Analytical solutions for the number of surviving malignant cells are obtained for special cases of slow and fast reoxygenation. The radiobiological effect of reoxygenation for different fractionation regimens is also evaluated numerically. In this study, a radiobiological model for kinetics of reoxygenation in tumors is used to evaluate different fractionation schedules in radiotherapy of prostate cancer. The obtained results indicate that in the case of low alpha/beta ratio for malignant cells (e.g., =1.5Gy), treatment schedule with 4-10 fractions and dose per fraction >4-5Gy can result in increased cell kill in the treatment target at the same level of rectal toxicity as compared to conventional fractionation. The findings of this study also suggest that radiotherapy of the prostate with 1-3 fractions can be radiobiologically inferior to treatments with greater number of fractions.

Results of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. Comparative efficiency of hypofractionation and classical fractionation schedules

Objective: comparison of the effectiveness of the results of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer using classical and hypofractionated schedule of radiation therapy.Materials and methods. This study is based on a retrospective analysis of a database of patients with locally advanced rectal cancer (T3C–D, positive circumferential resection margin or T4) who underwent a prolonged course of neoadjuvant chemoradiotherapy followed by surgery. The patients were divided into two groups: the first (main) group, 71 patients who received a course of chemoradiotherapy in hypofractionation schedule as part of neoadjuvant treatment (4 Gy × 40 Gy, 3 fractions per week) in combination with chemotherapy with capecitabine 1650 mg / m2 in two doses on weekdays. The second group (control group) included 79 patients who treated with long-course chemoradiotherapy in the classic fractionation mode (2 Gy × 50–58 Gy, 5 fractions per week) in combination with chemotherapy with capecitabine 1650 mg / m2 in two doses on weekdays. In the preoperative period, along with chemoradiotherapy, 4–8 courses of the systemic chemotherapy in the CapOx mode was used. The primary endpoint of this study was pathological complete response. Secondary endpoints included the seve rity of early radiation and hematological toxicity, the incidence of local recurrence, distant metastases, overall and disease-free survival. Results. The study included 150 patients. The overall frequency of acute radiation toxicity of grade III–IV was 5.6 % in the main group and 8.9 % in the control group (p = 0.658), from them hematological toxicity – 2.82 % and 7.6 %, respectively (p = 0.350), skin and pelvic organ toxicity – 2.82 % and 1.3 %, respectively (p = 0.926). Complete pathological response of III degree in the groups achieved 22.5 % and 19 %, respectively (p = 0.593), grade IV – 18.3 % and 15.2 %, respectively (p = 0.829). In the main and control groups, 4.2 % and 3.8 % of local recurrence were registered, respectively (p = 0.954; hazard ratio (HR) 1.05; 95 % confidence interval (CI) 0.21–5.22). The median time of disease-free survival was 39.4 months. The three-year disease-free survival in the main group was 73.2 % and in the control group 64.6 %, respectively (p = 0.353; HR 0.79; 95 % CI 0.42–1.35). The three-year overall survival in the main and control groups were 84.5 % and 82.3 %, respectively (p = 0.743; HR 0.87; 95 % CI 0.39–1.92). Conclusions. The hypofractionation schedule can be considered as an alternative and not inferior to the standard dose fractionation regimen in a prolonged course of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

Breast Cancer Molecular Subtype as a Predictor of Radiation Therapy Fractionation Sensitivity

The predictive benefit of breast cancer molecular subtypes for systemic therapy approaches has been well established; yet, there is a paucity of data regarding their use as a predictor of radiation therapy fractionation sensitivity. The purpose of this study was to determine whether rates of local recurrence (LR) for patients treated with hypofractionated (HF) radiation therapy, in comparison to conventional fractionation, differ across breast cancer molecular subtypes in a large, prospectively collected cohort treated with modern systemic therapy. Patients who received a diagnosis of stage I-III breast cancer between 2005 and 2009 were identified. Molecular subtype was determined using the American Joint Committee on Cancer classification system (luminal-A, luminal-B, HER2+, triple negative [TN]). Multivariable Cox regression modeling was used to identify predictors of LR. LR-free-survival (LRFS) was determined using the Kaplan-Meier method and compared using the log-rank test. A total of 5868 cases were identified with a median follow-up of 10.8 years. Patients with luminal-A subtype composed 45% of the cohort (n = 2628), compared with 30% luminal-B (n = 1734), 15% HER2+ (n = 903), and 10% TN (n = 603). A total of 76% (n = 4429) of patients were treated with HF. The 10-year LRFS was 97.1% (95% confidence interval [CI], 96.6-97.6) for the whole cohort. The 10-year LRFS based on molecular subtypes was 98.3% (95% CI, 97.6-98.7) luminal-A, 96.6% (95% CI, 95.5-97.4) luminal-B, 97.0% (95% CI, 95.5-98.0) HER2+, and 93.5% (95% CI, 91.1-95.3) TN (P < .001). There was no difference in the 10-year LRFS between patients treated with HF versus conventional fractionation among those with luminal-A (98.2% vs 98.4%; P = .42), luminal-B (96.6% vs 96.8%; P = .90), HER2+ (97.5% vs 95.8%; P = .12), or TN (93.9% vs 92.2%; P = .47). There was no significant interaction between subtype and fractionation regimen. These data support the routine use of hypofractionated radiation therapy regimens across all breast cancer subtypes.

An overview of superficial radiation of surgical keloidectomy sites to reduce keloid recurrences

AbstractBackgroundKeloids adversely impact medical, cosmetic and psychological health and are detrimental to the quality of life of those affected. The clinical challenge following surgical excision of keloids is the high, 71%, recurrence rate. Based on its ability to suppress wound healing, judicious use of low‐dose, fractionated superficial radiation therapy (SRT) has been successful in reducing post‐keloidectomy keloid recurrences.ObjectiveThis overview focusses on the reported safety and efficacies of differing dosing and fractionation regimens of SRT of keloidectomy surgical sites to reduce keloid.MethodsA literature review regarding superficial radiation of surgical keloidectomy sites to reduce keloid recurrences.ResultsPostsurgical treatment of keloid excision suture lines with several fractions of SRT reduces keloid recurrence rates. An effective and safe treatment protocol is a biologically effective dose of 3000 cGy (BED 30) with three fractions of 600 cGy on postoperative days 1, 2, and 3. Fractionation of the SRT dose reduces the risk of hyperpigmentation and other adverse events.ConclusionJudicious use of low‐dose, fractionated superficial radiation therapy safely and effectively reduces the rate of post‐keloidectomy keloid recurrences.

Use of a Radiation Tumor Bed Boost After Breast-Conserving Surgery and Whole-Breast Irradiation: Time Trends and Correlates

We sought to evaluate time trends and correlates of the use of a radiation tumor bed boost (TBB) after breast-conserving surgery and either conventional or hypofractionated whole-breast irradiation (CWBI or HWBI) for patients with early stage breast cancer. The National Cancer Database was queried for patients diagnosed between 2012 and 2016. We evaluated the utilization of TBB before and after publication of the Society of Surgical Oncology-American Society for Radiation Oncology margin guidelines in relation to sociodemographic variables, treatment facility, tumor characteristics, and whole-breast fractionation. The population included 380,387 patients, of whom 76.7% received a TBB. Utilization of TBB decreased over time (2012-2013: 79.2%; 2014: 76.6%; 2015-2016: 74.7%; P < .001); this was seen for most subgroups evaluated. Rates of TBB differed by facility type and region. There was a decrease in TBB use in patients treated with CWBI over time (2012-2013: 84.9%; 2014: 83.5%; 2015-2016: 82.3%; P < .001) but an increase among patients treated with HWBI (2012-2013: 55.5%; 2014: 60.7%; 2015-2016: 65.1%; P < .001); this was also seen for low-risk patients (age >70 years, negative margins). Among patients undergoing HWBI, TBB was more frequently used when 15 fractions were used compared with 16 fractions (76.8% vs 59.1%; P < .001). The use of TBB decreased over time, coinciding with the publication of new margin guidelines, for patients receiving CWBI and those with negative margins, but TBB use increased for patients treated with HWBI. Hence, fractionation regimen is a critical variable in analyzing changes over time in the practice patterns of TBB.

Variation in the use of radiotherapy fractionation for breast cancer: Survival outcome and cost implications

Background and purposeSubstantial variation in the adoption of hypofractionation for breast radiation therapy has been observed, despite the availability of consensus guidelines. This study aimed to investigate the variation in radiation therapy fractionation in breast cancer patients in New South Wales (NSW), Australia, and to estimate survival outcome and cost implications. Materials and methodsThis is a population-based cohort of patients who received radiation therapy for breast cancer (2009–2013), as captured in the NSW Central Cancer Registry. A logistic regression model was used to identify factors associated with fractionation type. Survival outcome was estimated using multivariable Cox proportional hazards model. Cost per treatment and potential cost saving associated with evidence-based fractionation was estimated. ResultsA total of 10,482 patients were available for analysis, divided into 3 cohorts (breast alone: N = 7000; breast + nodes: N = 1119; all chestwall: N = 2363). In multivariable analysis, increasing age, laterality (right), year of treatment (2013), early stage, lower socioeconomic status, and regional area of residence were independent predictors of hypofractionation for breast alone radiation therapy. For the breast + nodes and chest wall cohorts, common factors that predicted the use of hypofractionation were increasing age. In multivariable survival analysis, there was no difference between the fractionation regimens at 5 years. Estimated radiation therapy cost of this cohort approximated $52.1 million, compared with $38.5 million had these patients been treated with evidence-based fractionation. This demonstrated a potential saving of $13.6 million. ConclusionHypofractionation appears underused for breast radiation therapy in NSW over time. This study highlights that evidence-based practice will translate to reduced health care treatment costs.

Adrenal SBRT: a multi-institutional review of treatment outcomes and toxicity.

The adrenal glands are a common site of metastatic disease. Definitive treatment for oligometastatic disease using ablative radiotherapy is becoming common in modern radiation oncology practice. However, most data on the treatment of adrenal metastases are limited to single institution reports. Furthermore, delivering ablative radiotherapy doses to intra-abdominal lesions can be challenging due to the proximity of the gastrointestinal tract. We report the outcomes of a multi-institutional cohort of patients treated with definitive radiotherapy for adrenal metastases, primarily using 10 fraction regimens. Retrospective review of institutional databases revealed 29 lesions in 27 patients were treated from 2005 to 2018 at two institutions. Outcome data, including local control, disease-free, and overall survival were abstracted from the medical record system. Toxicity was graded using CTCAE v5.0. Detailed radiotherapy data was abstracted from the treatment planning systems. The median dose was 50Gy in 10 fractions. Actuarial 1 and 2year local control was 86% and 76% respectively. The median overall and disease-free survival were 22.8 and 5.6months respectively. There were no associations identified between local failure and GTV and PTV physical or biologic effective dose. Two patients developed late Grade 3 gastrointestinal toxicity. High dose radiotherapy to adrenal metastases is a feasible treatment with excellent local control and a reasonable safety profile. For lesions in close proximity to gastrointestinal structures, moderately hypofractionated 10 fraction regimens may be a reasonable compromise between local control and toxicity.

A tumor-immune interaction model for hepatocellular carcinoma based on measured lymphocyte counts in patients undergoing radiotherapy

PurposeThe impact of radiation therapy on the immune system has recently gained attention particularly when delivered in combination with immunotherapy. However, it is unclear how different treatment fractionation regimens influence the interaction between the immune system and radiation. The goal of this work was to develop a mathematical model that quantifies both the immune stimulating as well as the immunosuppressive effects of radiotherapy and simulates the effects of different fractionation regimens based on patient data. Methods and materialsThe framework describes the temporal evolution of tumor cells, lymphocytes, and inactivated dying tumor cells releasing antigens during radiation therapy, specifically modeling how recruited lymphocytes inhibit tumor progression. The parameters of the model were partly taken from the literature and in part extracted from blood samples (circulating lymphocytes: CLs) collected from hepatocellular carcinoma patients undergoing radiotherapy and their outcomes. The dose volume histograms to circulating lymphocytes were calculated with a probability-based model. ResultsBased on the fitted parameters, the model enabled a study into the depletion and recovery of CLs in patients as a function of fractionation regimen. Our results quantify the ability of short fractionation regimens to lead to shorter periods of lymphocyte depletion and predict faster recovery after the end of treatment. The model shows that treatment breaks between fractions can prolong the period of lymphocyte depletion and should be avoided. ConclusionsThis study introduces a mathematical model for tumor-immune interactions using clinically extracted radiotherapy patient data, which can be applied to design trials aimed at minimizing lymphocyte depleting effects in radiation therapy.

Evaluating reimbursement of skin radiation therapy: Technique and fractionation

PurposeMultiple skin radiation therapy techniques exist including electron beam therapy, high-dose-rate (HDR) brachytherapy, superficial/orthovoltage, and electronic brachytherapy (EB). The purpose of this analysis was to compare reimbursement between these modalities by fractionation regimen. Methods and MaterialsReimbursement was derived from the 2020 Medicare Physician Fee Schedule by fractionation schedule or from the 2020 Hospital Outpatient Prospective Payment national benchmarks. A secondary analysis evaluating incorporation of daily simulation codes was also performed to factor in coding heterogeneity. ResultsSuperficial/orthovoltage was the least costly and EB the next least costly technique regardless of fractionation. When incorporating variations in coding of simulations, reimbursement with superficial/orthovoltage was still least costly, with a reduction in cost of $1,755, $2,715, $5,076, and $7,436 compared with HDR brachytherapy for 6, 10, 20, and 30 fractions, respectively, and a reduction in cost of $1,325, $2,170, $4,281, and $6,392 compared with EB. HDR brachytherapy and EB costs can increase by 63–110% based on nonrecommended variation in daily simulation billing, with superficial/orthovoltage experiencing the highest relative increase. Reimbursement per course can vary by a factor of 4.5–9.3x depending on the modality and fractionation scheme utilized. ConclusionsSuperficial/orthovoltage followed by EB were the least costly modalities with regard to reimbursement; however, costs can vary with frequency of simulation code billing. Consistency and standardization in skin radiation therapy reimbursement is needed, and case rates within a radiation oncology alternative payment model may help to minimize reimbursement heterogeneity among treatment options.

Predictors of Whole Breast Radiation Therapy Completion in Early Stage Breast Cancer Following Lumpectomy

BackgroundWhole breast radiation therapy (RT) has become standard of care in early stage breast cancer treatment following lumpectomy. Predictors of RT completion have been sparsely studied, with no previous nationwide examination of the impact of fractionation regimen on completion rate. Patients and MethodsThe National Cancer Database identified patients with early stage breast cancer having undergone lumpectomy and RT from 2004 through 2015. Fraction size of 1.8-2.0 Gray (Gy) was defined as standard fractionation (SFRT); 2.66-2.70 Gy/fraction as hypofractionation (HFRT). RT completion was defined as receipt of at least 46 Gy for SFRT and 40 Gy for HFRT. A multivariable logistic regression model characterized RT completion predictors. ResultsA total of 100,734 patients were identified where fraction size could be reliably characterized as above; more than 87% completed RT. Of these, 66.8% received SFRT, yet HFRT use significantly increased over time (5.2% increase/year; P < .0001). RT completion rates were significantly greater following HFRT (99.3%) versus SFRT (79.7%); patients receiving SFRT had higher odds of not completing RT (odds ratio, 41.5; 95% confidence interval, 36.6-47.1; P < .0001). Multivariable analysis revealed that African-American and Caucasian patients treated with SFRT versus HFRT had 22 and 43 times the odds of not completing RT, respectively (P < .0001). ConclusionsSFRT remained the majority of RT fractionation in the studied time period, although HFRT use has increased over time. Patients residing > 10 miles from a treatment facility or of African-American race had lower odds of completing RT, as were patients treated with SFRT versus HFRT. These findings suggest compliance advantages of HFRT for patients with early stage breast cancer having undergone lumpectomy.

Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AimsChoosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. Materials and methodsA retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. ResultsUnivariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), ‘lifelong never’ smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. ConclusionIn this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1.

NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.