Fractionation Regimens Research Articles

Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data.

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93-1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90-1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91-1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.

P53 Modulates Radiosensitivity in Head and Neck Cancers-From Classic to Future Horizons.

p53, initially considered a tumor suppressor, has been the subject of research related to cancer treatment resistance in the last 30 years. The unfavorable response to multimodal therapy and the higher recurrence rate, despite an aggressive approach, make HNSCC a research topic of interest for improving therapeutic outcomes, even if it is only the sixth most common malignancy worldwide. New advances in molecular biology and genetics include the involvement of miRNA in the control of the p53 pathway, the understanding of mechanisms such as gain/loss of function, and the development of different methods to restore p53 function, especially for HPV-negative cases. The different ratio between mutant p53 status in the primary tumor and distant metastasis originating HNSCC may serve to select the best therapeutic target for activating an abscopal effect by radiotherapy as a "booster" of the immune system. P53 may also be a key player in choosing radiotherapy fractionation regimens. Targeting any pathway involving p53, including tumor metabolism, in particular the Warburg effect, could modulate the radiosensitivity and chemo-sensitivity of head and neck cancers.

"Big Boom" (4 Gy x 1) Radiation Treatment (RT) Versus "Big Boom" (2 Gy x 2) for Non-Hodgkin Lymphoma (NHL)

Purpose/Objectives Indolent lymphomas are exquisitely sensitive to radiation. Recently, programs of only 4 Gy in 2 daily fractions (Boom-Boom) were shown to be highly effective in controlling irradiated site(s). During the COVID-19 pandemic, the International Lymphoma Radiation Oncology Group (ILROG) proposed guidelines that allowed substitution of the Boom Boom (2 Gy x 2) regimen with Big Boom single fraction regimen of only 4 Gy. This report compares our center's experience with Big Boom to Boom-Boom. Materials/Methods All consecutive indolent lymphomas were included. After April 2020 both options of very low dose as well as choice of a standard full dose of 24 Gy were discussed with the patient and choice was made with consideration of access logistics, patient preference as well as disease site(s). Patients were treated with a definitive or palliative intent depending on disease stage and prior therapy exposure. Patients treated with 24 Gy are not included in this report. Overall response rate was assessed with Lugano PET criteria at the initial post-RT imaging. Differences between the two groups were examined using the Fisher's exact test and Mann-Whitney test. Results We evaluated a total of 440 lesions in 363 patients, including 142 lesions (32%) treated with 4 Gy x 1 ("Big Boom") and 298 lesions (67%) treated with 2 Gy x 2 ("Boom Boom"). Table 1 summarizes the patient and treatment characteristics. Patient age at the time of RT, sex, and the proportion of treated lesions with maximum axial diameter of greater than 5 cm were not significantly different between the two groups. Marginal zone lymphoma comprised 27% of each cohort. The Big Boom cohort was more likely to have follicular lymphomas (66% vs 52%, p = 0 .003), though the proportion of higher-grade follicular lymphomas was similar between cohorts. The overall response rate was 87% for both groups at the first post-RT evaluation (median of 2 months from RT for both cohorts). Furthermore, there was no significance difference in the rate of complete response, partial response, stable disease, or progressive disease between the cohorts at initial post-RT imaging. For both regimens, no directly related short-term side effects were observed. Conclusions Both the Big Boom and Boom Boom regimens demonstrated excellent overall response rates at the initial post-RT imaging assessment among patients with indolent lymphomas. While longer term follow-up is required to confirm durability of these findings, our initial experience suggests that the single dose, single visit Big Boom regimen (4 Gy x 1) recommended by ILROG during the Covid-19 pandemic is an effective treatment approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PO21: Commissioning of an HDR Universal Endometrial Applicator Set

<h3>Purpose</h3> To commission for HDR brachytherapy a Varian CT/MR compatible universal endometrial applicator set used to treat inoperable endometrial cancer (i.e., vagina, cervix, paracervical area, endometrium, uterus, and ovaries), and to develop all necessary documents and procedures for clinical implementation. The kit contains a straight central tandem, Left/Right tandems (20 deg. angle, 60, 70, and 80 mm length), clamping unit, and a vaginal cylinder with lever. <h3>Materials and Methods</h3> The tests performed for commissioning and clinical implementation are described in the following. <i>Functionality tests</i>: All kit components were checked for structural integrity. The applicator was assembled using the information received from the manufacturer. A GYN source guide tube (SGT) was connected to each tandem and the total length was checked using the gauge wire. GYN dummy wires were placed inside tandems and digital radiographic images (kVp 85, mA 80, ms 200, small focal spot, no buildup) were acquired to check the pathway and assess for any obstruction. <i>Autoradiographs</i>: A piece of XR-SP2 GafChromic film was placed on the conventional simulator couch, then the seven tandems were placed over the film, with a 2-cm solid water slab used as buildup. Tandems were connected via GYN SGTs to the HDR unit and a test plan was delivered with 9 dwell positions/channel, 0.8 sec/position, starting at 129.5 cm distally, with a 1-cm step size. GYN dummy wires were then placed inside tandems and the film was exposed twice with 135 kV, 80 mA, 400 mAs. Alternation of source positions and dummy dots displayed on the film was assessed. <i>Clinical implementation tests</i>: The applicator was assembled and placed in a small water-filled container and CT-scanned with GYN dummy wires inserted in each tandem. Sagittal/Coronal T2 and Axial MDIXON MR images were acquired for the applicator (without dummy wires) using a 1.5 T scanner. The CT and MR images were imported to Eclipse and rigidly registered, matching the tandems and cylinder. The device can be clinically used with two or three tandems. Test plans were generated for all clinical scenarios. Radiation Oncologists provided information regarding planning goals and fractionation regimen (number of fractions/number of implants, Rx dose). The physics team generated all necessary documents and procedures for clinical implementation. <h3>Results</h3> All set components were found to be functional with no obstruction. Their length was within 1 mm from nominal. Autoradiographs showed that source positions were within 1 mm from designed locations. To simulate a clinical scenario, a CTV was contoured to cover "cervical area" (above cylinder), entire "uterus" (up to the tip of the tandems), and a portion of the "upper vagina" (a portion of the cylinder). The tandems were manually digitized, paying attention to their curvature on sagittal and coronal images. The applicator was also loaded from the library of applicators to assess if that approach is more efficient than manual digitization. We found that Left and Right tandems loaded from the library are reversed (Varian was notified). An HDR plan was generated, assuming 500 cGy/fraction. The three tandems were loaded with sources inside the CTV and the plan was 3D optimized to cover the CTV with D90>90%. The process was repeated for combinations of two tandems. Treatment and Plan checklists, a BED Cumulative form, and a Planning Note document were developed, to be evaluated and refined after the first clinical case. A live demo with a manufacturer representative was organized to discuss the applicator assembly/disassembly in the OR setting. Sterilization procedures were developed based on the manufacturer's instructions. An in-service was organized for therapists/nurses, and pre-treatment huddles will be incorporated into the process for the first several cases. <h3>Conclusions</h3> The applicator set was validated and procedural documents are ready for clinical use. Coronal MRI series proved to be essential for the CT-MR registration process and tandem digitization. Via dose shaping, the dose distribution can be fine-tuned and adjusted to cover a longer portion of the upper vagina if needed. Also, a differential prescription may be used, as needed, for the uterus and upper vagina. The ability to rotate and shift the tandems allows adaptation to patient anatomy. An annual QA procedure was developed, including the tests performed for commissioning. A 3D printed holder with a 2-cm buildup was designed to ensure consistency in the autoradiographs.

Saturday, June 18, 20223:45 PM - 4:45PM MSS01 Presentation Time: 3:45 PM: A Single-Institution Retrospective Study of Three-Fraction HDR Accelerated Partial Breast Irradiation

<h3>Purpose</h3> Accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy is a standard of care treatment which is typically delivered over 8-10 fractions. The TRIUMPH-T multi-institutional study recently demonstrated promising results using a shorter three fraction regimen. However, there are limited additional published series using this regimen. Here, we report our experience and outcomes for patients treated as per the TRIUMPH-T regimen. <h3>Materials and Methods</h3> Retrospective single-institution analysis of patients who underwent lumpectomy followed by APBI (22.5 Gy in 3 fractions delivered over 2-3 days) using a SAVI applicator between November 2016 and January 2021. Per the TRIMPH-T protocol guidelines, the planning treatment volume (PTV) was 1 cm beyond the surgical cavity, limited to 0.5 cm from the skin surface, and subtracted from chest wall and SAVI cavity. Dose-volume metrics were obtained from the clinically treated plan. Chart review was performed to determine locoregional recurrence and toxicities according to CTCAEv5.0. <h3>Results</h3> From 2016-2021, 31 patients were treated per the TRIUMPH-T protocol. The median age was 64 years (range 46-82). 77% of patients had invasive ductal carcinoma, median tumor size was 1.2 cm (range 0.4-2.0), 84% were Grade 1-2, 90% were N0 (3 DCIS patients were Nx), and 100% were ER+. Median follow-up was 31 months (range 6-62 months) from completion of brachytherapy. PTV median dose metrics were as follows: D90: 94.6% (range 90-110%), V150: 22.0cc (range 12.5-38.2cc), V200: 11.0cc (range 3.5-21.2cc), and DHI: 0.51 (range 0.36-0.68). Median D0.03cc for the skin (3 mm inner margin on body) and rib were 68.3% (range 29.9-91.6%) and 70.6% (range 15.7-124.2%), respectively. There were no acute/late grade 3 or higher toxicities. Cumulative late Grade 1 and 2 toxicities were seen in 58% and 6% of patients, respectively. Grade 1-2 fibrosis was seen in 32% of patients. Other toxicities included grade 1 breast pain (26%), grade 1-2 seroma formation (23%), grade 1 hyperpigmentation (6%), symptomatic fat necrosis (6%), and breast infection (3%). Of note, four patients experienced locoregional recurrence: three ipsilateral breast tumor recurrences (two in the same quadrant as the lumpectomy cavity), and one nodal recurrence (patient was cN0/pN0). All three ipsilateral breast tumor recurrences occurred in patients who would be classified as "cautionary" based on ASTRO consensus guidelines due to age ≤50, lobular histology, or high grade. There were no distant recurrences or deaths of any cause. <h3>Conclusions</h3> Three-fraction HDR brachytherapy APBI delivered per the TRIMUPH-T protocol was well-tolerated in our cohort with no grade 3 or higher toxicities and an acceptably small percentage of grade 2 toxicities. Given the small sample size, the number of recurrences suggests that attention to appropriate patient selection is necessary until more long-term follow-up data is available.

National Trends in Definitive Radiation for Large Unresected cT3N0 Non-Small Cell Lung Cancer Tumors

<h3>Purpose/Objective(s)</h3> The ideal approach to radiation regimens for patients with unresected cT3N0 non-small cell lung cancer (NSCLC) tumors >5cm is undefined. We queried the National Cancer Database to investigate patterns of care and outcomes for this unique subset of patients treated with definitive radiation. <h3>Materials/Methods</h3> Patients with cT3N0M0 NSCLC diagnosed between 2004-2018 and a documented tumor diameter >5cm were included. Patients who underwent surgery were excluded. Conventional fractionation (CF) was defined as 59.40-70.20Gy in 30-39 fractions, hypofractionation (HF) as 45-70Gy in 8-15 fractions, and stereotactic body radiation therapy (SBRT) as 40-60Gy in 3-5 fractions. Patient characteristics and clinical factors were evaluated. Chi-Square test was used to compare frequency distributions between categorical variables. Kaplan-Meier with log-rank test was used to assess overall survival (OS) and multivariable Cox regression was performed to assess the impact of covariates on OS. <h3>Results</h3> A total of 4,047 patients met study criteria. Median age was 72 years and median tumor size was 6.5cm. Of these patients, 3172 (78%) were treated with CF, 290 (7.2%) with HF, and 585 (14.6%) with SBRT. Patients treated with SBRT were more likely to be younger (p<0.001), white (p<0.001), live farther away from the treatment center (p=0.049), have Medicare insurance (p<0.001), receive treatment in an academic center (p<0.001) located in a metropolitan region (p<0.037), have a higher Charlson-Deyo Comorbidity (CDC) score (p<0.001), and have a lower lobe primary tumor (p<0.001). With a median follow up of 18.89 months, median OS was 20.78 months (IQR: 10.41-42.91) for patients treated with CF, 20.36 months (IQR: 10.55-32.10) for HF, and 23.86 months (IQR: 11.43-42.78) for SBRT, which was significantly different on Kaplan-Meier analysis (p<0.025). However, there was no difference in OS among fractionation regimens on multivariate analysis. Female gender, African American race, and treatment center distance between 9.5-23.2 miles were associated with improved OS, with greatest impact observed for academic centers (HR 0.863, 95% CI 0.792-0.939; p < 0.001) and other non-white race (HR 0.742, 95% CI 0.566-0.974; p = 0.31). Factors associated with worse OS were age >77 years (HR 1.332, 95% CI 1.166-1.521; p < 0.001) and any CDC score (score of ≥3: HR 1.431, 95% CI 1.215-1.684; p < 0.001). <h3>Conclusion</h3> Conventional fractionation was utilized most frequently to treat large (>5cm) cT3N0 NSCLC tumors not undergoing surgical management. There was no difference in overall survival among conventional, hypofractionated, and SBRT regimens.

Effectiveness and Toxicity of Re-Irradiation after Breast Conserving Surgery for Recurrent Breast Cancer: A Multi-Institutional Study

<h3>Purpose/Objective(s)</h3> Breast re-irradiation (reRT) after repeat breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy in women presenting with low risk in-breast tumor recurrence (IBTR). However, there is limited data on optimal patient selection and safety of different fractionation regimens. This multi-institutional study reports safety and efficacy in a large cohort of women with IBTR treated with repeat BCS and reRT. <h3>Materials/Methods</h3> Using electronic medical record search tools, we identified all patients who underwent repeat BCS followed by breast reRT from 2015-2021 at 2 institutions. Univariate logistic regression models were used to identify clinical and dosimetric factors associated with development of acute and late toxicities. All statistical tests were two-sided, and the null hypothesis was rejected for p<0.05. Kaplan Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS) and locoregional recurrence-free survival (LR-RFS). <h3>Results</h3> We identified 66 patients with an IBTR treated with repeat BCS. In the initial RT course, 55% received whole breast RT (WBI) with conventional fractionation (≤2 Gy/fraction[fx]), 29% WBI with hypofractionation (2.6-2.7 Gy/fx), 6% partial breast irradiation (PBI) ultrahypofractionation (6-8 Gy/fx) and 11% had unavailable treatment details. There was a median of 11 years between initial breast cancer and IBTR. At time of recurrence, 36% of patients had tumors located in the same quadrant as the initial cancer, 41% had invasive carcinoma with ductal carcinoma in situ (DCIS), 41% had invasive carcinoma alone, 18% had DCIS alone, 92% had tumors < 2 cm, 68% had low-intermediate grade tumors and all were clinically node negative. For reRT, 95% received PBI (57.5% 45 Gy/1.5 Gy twice daily; 27% 45 Gy/1.8 Gy daily; 10.5% hypofractionation), and 5% received WBI (45-46.8 Gy in 1.8 Gy/fx), all of whom had received PBI for the initial course. Nine patients (13%) underwent adjuvant chemotherapy and 44 (67%) adjuvant hormone therapy. Median follow-up was 16 months (range 3-60). Twenty-one patients (32%) experienced any acute ≥ grade 2 events, and 17 (26%) experienced any late ≥ grade 2 toxicities. One patient experienced grade 3 fibrosis and one patient experienced grade 3 telangiectasia at 36 months. None had grade 4 or higher late adverse events. We found no association between fractionation of reRT or cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. <h3>Conclusion</h3> In this large multi-institutional series of patients with recurrent breast cancer, second breast conservation surgery followed by reRT was effective with no local recurrences and excellent disease control outcomes, and toxicity appears to be acceptable. Longer follow-up and more prospective study are needed to further inform patient selection and establish the efficacy and tolerability of repeat breast conservation therapy in the setting of limited, low-risk recurrence.

Impact of Facility Case Volume on Radiation Schema and Outcomes in Palliative Radiation of Osseous Metastases

<h3>Purpose/Objective(s)</h3> To compare how facility volume impacts palliative RT practices in patients with osseous metastases, radiation schema used, and outcomes of the applied therapies by analyzing the percentage of remaining life spent receiving RT (PRLSRT) and RT completion rates. <h3>Materials/Methods</h3> A retrospective analysis was conducted using the National Cancer Database (2010-2016). Facilities were grouped and analyzed according to case volume of patients treated with palliative RT for bone mets. Facilities were grouped by case volume (<10, 10-24, 25-49, 50-74, 75-99, 100-149, ≥150). Patterns of palliative RT schemes (extended fractionation (>10 fx), hypofractionation (5 or fewer), and single fraction (8 Gy)) and outcomes were evaluated for facilities based on case volume. PRLSRT and course completion rates were calculated. <h3>Results</h3> 52,864 patient cases from 1,312 facilities were included. Higher facility case volume was associated with facility type (Academic > Comprehensive Community > Integrated Network > Community Cancer Program), higher population areas, higher distance traveled for treatment, lower comorbidity, younger age, and private insurance. Higher volume facilities were associated with the use of higher dose per fraction, resulting in increased use of single fraction, hypofractionation, and less use of extended fractionation regimens (see Table 1). The use of shorter courses at high volume centers resulted in increased radiation completion rates, and remaining life spent receiving radiation. <h3>Conclusion</h3> For palliative treatment of osseous metastases, facilities with higher case volumes favor shorter courses of RT and have better outcomes measured by PRLSRT and higher rates of treatment completion. It should be considered whether facility volume and experience influence the adoption of hypofractionation for palliative treatment of bone mets and how to improve adoption of shorter courses among all volume facilities.

The Impact of Implementing Hypofractionation Prescription Regimens and Modernizing Delivery Technique on Treatment Resources in Breast Radiotherapy

<h3>Purpose/Objective(s)</h3> To determine the change in treatment resources due to the implementation of hypofractionated prescription regimen <h3>Materials/Methods</h3> All patients between January 1, 2012 and December 31, 2021 receiving curative intent breast radiotherapy at a tertiary cancer center were included. Plan and patient data were extracted from the patient database with the treatment planning system and direct database query. Treatment plan categorization was completed using data elements to include only curative intent. Treatment plans for seroma boost or supraclavicular irradiation were excluded to ensure this analysis did not double-count regional nodal irradiation contribution or confound boost with hypofractionation. Treatment delivery time is recorded in the database for each patient treatment delivered. Average patient treatment time per year was estimated by multiplying the average fractions each year by average time in the same year. The standard fractionation regimens (95% of patients) are 42.56 Gy in 16, 40 Gy in 16, 27 Gy in 5 (accelerated partial breast irradiation), and 26 Gy in 5 (FAST-Forward). In the analysis, implementation milestones are indicated for new prescription regimens and delivery technique changes including deep inspiration breath hold (DIBH) for left-sided patient treatments and daily verification imaging. <h3>Results</h3> A total of 6505 patients were included. Table 1 details the total number of patients per year, the average number of fractions treated per patient, and the average treatment time of each patient plan. The average total fractions per treatment decreased from 17.5 in 2012 to 10.9 in 2021. The average treatment delivery time increased from 12.9 minutes to 21.4 minutes. <h3>Conclusion</h3> In considering total treatment resources, the interplay between hypofractionation and modernization delivery techniques is complex. The impact of hypofractionation reduced the average number of fractions but total treatment resources are offset with the implementation of modern treatment delivery techniques. Hypofractionated prescription regimens reduce the time and travel commitment required of patients on an individual basis, contributing to person-centered care.

Stereotactic Ablative Radiotherapy for the Treatment of Pancreatic Metastases from Renal Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Glandular metastases, in particular pancreatic metastases, are associated with renal cell carcinoma (RCC) of indolent biology. Pancreatic metastases may develop in isolation or involve other organs and are associated with prolonged survival. Pancreatic metastases can be treated with systemic therapy, stereotactic ablative radiotherapy (SAbR) or surgical resection and the optimal management of these patients is unknown. There is a paucity of data on SAbR for RCC pancreatic metastases. Here, we report local control (LC), progression-free survival (PFS), overall survival (OS) rates as well as toxicities related to SAbR for RCC metastases to the pancreas. <h3>Materials/Methods</h3> This IRB-approved, single-institution, retrospective study included patients with RCC metastases to the pancreas treated with SAbR. Data on patient demographics, functional status, tumor characteristics, International Metastatic RCC Database Consortium (IMDC) risk category, local and systemic treatments, toxicities, and outcomes were collected and analyzed. RECIST 1.1 principles were utilized to determine LC rates and PFS. PFS was defined from the initiation of SAbR to progression (at SAbR-treated or other sites), or death. OS was defined from the start of SAbR to death. Two independent reviewers assessed patient electronic health records for toxicities using CTCAE v5 and relatedness scores. <h3>Results</h3> Twenty pancreatic metastases were treated with SAbR in sixteen RCC patients including 11 (69%) with favorable and 5 (31%) with intermediate-risk IMDC scores. Three patients (19%) were treatment naïve with oligometastatic disease, and thirteen (81%) were oligo-progressive on systemic therapy with 1-3 lines of prior systemic therapy. With a median follow-up of 35.9 months, LC was 90%. The two local failures observed occurred at 31.6 and 78.8 months following SAbR treatment. The median PFS was 12 months, 95% CI (3.3, 18.8), and the 2-year overall survival following pancreatic SAbR was 100%. The most common total dose and fractionation regimen utilized was forty Gray delivered over five fractions. The percentage of patients experiencing an acute grade 2 or 3 toxicity attributed to pancreatic SAbR was 6%. There was no acute grade >3 toxicities. The percentage of patients experiencing a late grade 2 or 3 toxicity was 12%. Median time to late adverse events was 42.5 months. <h3>Conclusion</h3> SAbR of RCC metastases to pancreas is feasible, safe and appears to be effective. Median PFS and 2-year OS in this cohort compared favorably to those reported in historical cohorts and is consistent with indolent disease.

Prospective Peer Review for Hypo-Fractionated Treatments During the COVID-19 Pandemic

Purpose/Objective(s)One of the measures taken in our department to minimize the risk of infection during the advent of the COVID-19 pandemic was to reduce the number of treatment fractions for appropriate disease sites. In this work we sought to assess peer-review grades for such hypofractionated cases during daily pre-dosimetric treatment planning multidisciplinary reviews as part of our ongoing quality control program.Materials/MethodsIn our multi-center radiation medicine department, prospective video-conferenced reviews are conducted daily on all cases requiring a new treatment plan by a multidisciplinary team using an in-house electronic whiteboard linked with our oncology-information systems. Each case is allocated a grade of A, B or C on the treatment directive and contours to respectively proceed with, suggest minor revisions, or to require major revisions prior to dosimetric treatment planning. The database was queried for the years 2017 through 2021 to assess trends of grades assigned for hypofractionated plans for comparison with those for conventional and SBRT plans for the same anatomic sites, for both pre-COVID (2017-2019) and COVID (2020-2021) years.ResultsOf the 7179 plans generated during this period for 11 anatomic sites, 980 were hypofractionated, 4823 were conventionally fractionated, and 1376 were SBRT plans with overall grade breakdown as follows: A: 69.9%, B: 30.0%, C: 0.1%. The fraction of B grades for conventional, hypofractionated and SBRT cases respectively were: Bladder (51.4%, 34.3%, -), Bone (10.5%, 13.0%, 35.7%), Brain (29.3%, 28.1%, 30.2%), Breast (20.9%, 19.8%, 100.0%), Endometrium (45.6%, 0.0%, -), Lung (30.1%, 26.7%, 34.3%), Pancreas (44.0%, 16.7%, 41.6%), Pelvis (29.0%, 100.0%, -), Prostate (33.5%, 24.5%, 36.4%), Rectum (40.9%, 21.9%, -), Skin (34.9%, 33.3%, -). For most sites, hypofractionated cases had lower fractions of B-grades and higher fractions of A grades compared with conventional or SBRT cases. The differences overall were not statistically significant (Mann-Whitney non-parametric test, p-value>0.05). Differences in grade fractions were minor in COVID versus non-COVID years. The only statistically significant differences noted in time trends were between hypofractionated cases versus SBRT cases for the bone sites (p-value 0.04).ConclusionReducing the fractionation regimens for appropriate anatomic sites during the COVID-19 pandemic yielded no major differences in prospective peer-review assessments compared with conventional or SBRT assessments. Peer review enabled continued resilience during the pandemic ensuring continuity of the quality of care.

NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer

<h3>Purpose/Objective(s)</h3> Randomized trials support a supplemental radiation dose (Boost) to the lumpectomy (L) cavity region after whole breast irradiation (WBI), providing a 20-30% relative reduction of in-breast recurrence (IBR); with the disadvantage that it extends treatment duration ⁓ 1 week. Hypofractionated WBI (H-WBI) in ≤ 3 weeks is used after L to deliver adjuvant WBI with acceptable toxicity and comparable IBR as conventional WBI (C-WBI) 50 Gy in 2 Gy fractions (F). NRG RTOG 1005 sought to determine whether a boost delivered concomitantly with H-WBI over 15 F is non-inferior for IBR compared to boost delivered sequentially after C-WBI in patients (pts) considered at High Risk of IBR. <h3>Materials/Methods</h3> Protocol-specified High Risk pts post L with stages 0, I & II breast cancer were randomized to C-WBI 50 Gy in 25 F or 42.7 Gy in 16 F plus sequential boost of 12 Gy in 6 F or 14 Gy in 7 F (Arm I) or H-WBI 40 Gy in 15 F plus concomitant boost of 8 Gy in 15 F of 0.53 Gy per day (Arm II). Radiation was target based 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT) and quality review (QA) was required. Stratification was by age (<50 vs ≥ 50), adjuvant chemotherapy (Y vs N), ER status (+ vs -) and histologic grade (1, 2 v 3). The primary endpoint is IBR. Assuming Arm I 5‐year IBR of 1.59%, 90% CI upper bound hazard ratio (HR) of 2.12 and 1‐sided significance level = 0.05, 2150 pts with at least 46 IBR events provide >80% power to conclude non‐inferiority. IBR was analyzed comparing the cause-specific hazards. Adverse Events (AE) were graded with NCI CTCAE v4. Physician-reported NRG-RTOG Global Cosmetic Score (GCS) was grouped as excellent/good vs fair/poor, and arms compared with chi-square. <h3>Results</h3> 2262 of 2354 randomized pts were eligible (Arm I n=1124; Arm II n=1138). Median age 55 years, 34% Stage II, 52% grade 3, 30% ER-, 17% close/+ margins consistent with a "High Risk" population. Radiation was 3DCRT 81%, IMRT 19%, and the QA was per protocol 81% and 88% on Arm I vs II, respectively. With a median follow-up of 7.3 years and 56 IBR events, the 5 and 7-year IBR were 2.0% and 2.2% on Arm I and 1.9% and 2.6% on Arm II. The non-inferiority comparison (Arm I reference level) resulted in a HR (90% CI): 1.32 (0.84, 2.05) and p = 0.039, thus meeting non-inferiority. No differences in AEs noted between arms, with low rates of ≥ grade 3 treatment-related AEs, 3.3% vs 3.5% for Arm I vs II, respectively (p=0.79). No difference in 3-year excellent/good cosmesis by arm: 86% for Arm I vs 84% Arm II (p=0.61). <h3>Conclusion</h3> Concomitant boost with H-WBI results in non-inferior IBR compared to sequential boost after C-WBI in high-risk cases and reduces overall treatment time. Using target based 3DCRT or IMRT, there are no differences in toxicity or cosmetic outcome for concomitant v sequential boost or the WBI fractionation regimen.

40 Gray in 5 Fractions for Salvage Re-Irradiation of Spine Lesions Previously Treated with Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> This is a retrospective single-center analysis of the safety and efficacy of re-irradiation to 40 Gray (Gy) in 5 fractions in patients previously treated with stereotactic body radiotherapy (SBRT) to the spine. <h3>Materials/Methods</h3> We identified 62 consecutive patients with various solid malignancies treated between January 2016 and December 2021 to 40 Gy in 5 fractions regardless of dose and fractionation at the first course of SBRT. Patients were followed clinically and with routine imaging. Acute (≤3 months) and late (>3 months) toxicities were assessed according to CTCAE v5.0. Local control was defined as absence of progression within the treated target volume. Time to progression was calculated from date of completion of SBRT to the date of an imaging study indicating progression. The probability of local progression before death was estimated using a cumulative incidence curve, and death without local progression was considered a competing risk. <h3>Results</h3> Most patients had oligometastatic disease (53.2%) and treated to the thoracic spine (51.6%). The most common fractionation regimen in the first course of SBRT was 27 Gy in 3 fractions, and the median time to re-irradiation was 13.1 months (range, 2.4-86.9 months). Twenty-four patients (38.7%) had surgery before re-irradiation. At time of simulation, 49 patients (79%) had epidural disease, including 19, 13, 12 and 5 patients with epidural spinal cord compression (ESCC) scale 1a, 1b, 1c and 2, respectively. Accordingly, myelogram simulations were performed in 82.2% of patients. Both the vertebral body and posterior elements were treated in 93.5% of patients. All early toxicities were low grade, apart from one case of grade 3 fatigue, one case of grade 3 diarrhea and one case of grade 3 pneumonitis. Five patients experienced a pain flare (8.1%). Two thirds of patients who reported pain at baseline, achieved improvement (33%) or complete resolution of pain (33%). About 40% of patients had at least a partial response in magnetic resonance imaging (MRI). At a median follow up time of 11.9 months (range, 1.8- 39.6 months), six patients (9.7%) suffered local progression. The median time to progression was 4.1 months (range, 1.93-13.8 months). The estimated incidence rate of local progression before death at 6-months and 12-months was 7%. Five patients (8.1%) developed radiation-related neuropathy (grade 1, 2 and 3 in two, one and two cases, respectively). No patient suffered grade 4 or higher late toxicity. The vertebral compression fracture rate was 16%. Three patients (4.8%) eventually underwent kyphoplasty and two patients underwent surgery (3.2%) for vertebral fractures. <h3>Conclusion</h3> Re-irradiation with 40 Gy in 5 fractions seems safe and effective for the salvage of lesions progressing after a previous course of SBRT in a cohort of patients with extensive disease involvement. Prospective randomized trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Changes in Fractionation Schedules for Breast Cancer Treatment during the COVID-19 Pandemic

Purpose/Objective(s)In 2020, 5-year results of the FAST-Forward trial and 10-year results for both the FAST trial and APBI-IMRT-Florence trials using ultrahypofractionated radiation (UHFR) were all published, each detailing equivalent outcomes for partial and whole breast UHFR schedules compared to more conventional fractionation regimes in early-stage breast cancer. Due to concerns over viral exposure, these treatment regimens were adopted in an effort to minimize patient exposure while achieving equivalent oncologic control. The purpose of this study was to compare the use of UHFR schedules for breast cancer patients before COVID-19, at the height of the pandemic and after widespread vaccination and analyze factors predictive of use.Materials/MethodsBetween October 2019 and February 2022, 733 patients with stage 0 or I breast cancer were offered radiation at our institution following breast conserving surgery. 43 patients were excluded (35 declined radiation and 8 received partial breast re-irradiation). We analyzed target volume (whole vs partial breast) and fractionation schemes (1 week vs 3 or more weeks) for 3 time periods of interest: pre-COVID-19 (October 2019-March 2020), height of COVID-19 (March 2020-March 2021) and post-COVID-19 vaccine (March 2021-February 2022). Fisher's exact test was used to compare frequencies of treatment parameters across groups and time periods. Logistic regression was used to determine factors associated with UHFR use. R (v4.1.2) was used for analysis.ResultsThe use of UHFR increased during the post-vaccine period as compared to pre-Covid-19 and the pre-vaccine time periods (p<0.001), with 4.6%, 9.2% and 23%, receiving UHFR respectively. On univariate analysis in the pre-vaccine time period, patients with grade 2 and 3 cancers were less likely to get UHFR (p = 0.003 and p = 0.005, respectively). Receiving radiation from an academic attending was associated with higher use of UHFR (p = 0.0004). On multivariate (MVA) patients with grade 2 and 3 disease remained less likely to get UHFR (p 0.001 and 0.004). Treatment by an academic attending remained a significant factor for use of UHFR (p=0.0003). In the post-vaccine time period, on univariate analysis, negative ER status and grade 3 tumors were associated with less use of UHFR (p = 0.04 and p = 0.0001, respectively). On MVA, only grade 3 was associated with less UHFR use (p = 0.0002).ConclusionDuring COVID there was a significant increase in the use of UHFR regimens for treatment of early-stage breast cancer patients at our institution that persisted and increased after the introduction of the vaccine despite return to pre-COVID patient volumes. Uptake of these new regimens was initially higher among academic radiation oncologists, however with education of community physicians and implementation of treatment planning scorecards, widespread adoption was seen.

Simulation-Free Radiation Therapy: An Emerging Form of Treatment Planning to Expedite Plan Generation for Patients Receiving Palliative Radiation Therapy

PurposeHerein we report the clinical and dosimetric experience for patients with metastases treated with palliative simulation-free radiation therapy (SFRT) at a single institution. Methods and MaterialsSFRT was performed at a single institution. Multiple fractionation regimens were used. Diagnostic imaging was used for treatment planning. Patient characteristics as well as planning and treatment time points were collected. A matched cohort of patients with conventional computed tomography simulation radiation therapy (CTRT) was acquired to evaluate for differences in planning and treatment time. SFRT dosimetry was evaluated to determine the fidelity of SFRT. Descriptive statistics were calculated on all variables and statistical significance was evaluated using the Wilcoxon signed rank test and t test methods. ResultsThirty sessions of SFRT were performed and matched with 30 sessions of CTRT. Seventy percent of SFRT and 63% of CTRT treatments were single fraction. The median time to plan generation was 0.88 days (0.19-1.47) for SFRT and 1.90 days (0.39-5.23) for CTRT (P = .02). The total treatment time was 41 minutes (28-64) for SFRT and 30 minutes (21-45) for CTRT (P = .02). In the SFRT courses, the maximum and mean deviations in the actual delivered dose from the approved plans for the maximum dose were 4.1% and 0.07%, respectively. All deliveries were within a 5% threshold and deemed clinically acceptable. ConclusionsPalliative SFRT is an emerging technique that allowed for a statistically significant lower time to plan generation and was dosimetrically acceptable. This benefit must be weighed against increased total treatment time for patients receiving SFRT compared with CTRT, and appropriate patient selection is critical.

Feasibility of anomaly score detected with deep learning in irradiated breast cancer patients with reconstruction

The aim of this study is to evaluate cosmetic outcomes of the reconstructed breast in breast cancer patients, using anomaly score (AS) detected by generative adversarial network (GAN) deep learning algorithm. A total of 251 normal breast images from patients who underwent breast-conserving surgery were used for training anomaly GAN network. GAN-based anomaly detection was used to calculate abnormalities as an AS, followed by standardization by using z-score. Then, we reviewed 61 breast cancer patients who underwent mastectomy followed by reconstruction with autologous tissue or tissue expander. All patients were treated with adjuvant radiation therapy (RT) after reconstruction and computed tomography (CT) was performed at three-time points with a regular follow-up; before RT (Pre-RT), one year after RT (Post-1Y), and two years after RT (Post-2Y). Compared to Pre-RT, Post-1Y and Post-2Y demonstrated higher AS, indicating more abnormal cosmetic outcomes (Pre-RT vs. Post-1Y, P = 0.015 and Pre-RT vs. Post-2Y, P = 0.011). Pre-RT AS was higher in patients having major breast complications (P = 0.016). Patients with autologous reconstruction showed lower AS than those with tissue expander both at Pre-RT (2.00 vs. 4.19, P = 0.008) and Post-2Y (2.89 vs. 5.00, P = 0.010). Linear mixed effect model revealed that days after baseline were associated with increased AS (P = 0.007). Also, tissue expander was associated with steeper rise of AS, compared to autologous tissue (P = 0.015). Fractionation regimen was not associated with the change of AS (P = 0.389). AS detected by deep learning might be feasible in predicting cosmetic outcomes of RT-treated patients with breast reconstruction. AS should be validated in prospective studies.

Weathering stage and topographic control on rare earth element (REE) behavior: New constraints from a deeply weathered granite hill

Rare earth elements (REE) are sensitive tracers of rock-water interactions and soil formation processes. In this study, we investigated the REE concentration and distribution patterns for both bulk samples and acid leachable phase for a series of regolith and soil profiles developed on a deeply weathered granite hillslope in a subtropical climate. The exogenous input had little impact on the REE distributions on the studied hillslope. The REE distribution in the profiles was controlled by changes in the physical and chemical environmental parameters and mineral transformation during weathering. However, the specific mechanisms differed among the different weathering stages and profiles located at different positions along the slope. Among the environmental parameters, the profile redox state and acidity were the dominant factors controlling the REE behavior, with organic materials as the main regulators. A strong positive relationship between chemical index of alteration (CIA) and La/Yb was observed for the regolith samples, but the La/Yb ratio decreased upward from a depth of 120 cm (the bottom depth of the soil horizon) as the CIA value increased, suggesting a preference for light REE (LREE) fixation in kaolinite formed during the dissolution of feldspar; however, a conversion occurred during the subsequent pedogenesis period. The hilltop soil profile was characterized by the strongest LREE depletion and the highest positive Ce anomaly (~7.31–14.28), compared with other profiles down the hillslope (~0.84–2.78). The strongest LREE depletion on the hilltop profile JLN-S4 suggested a preference for LREE release resulting from the transformation of kaolinite to gibbsite, and the highest Ce anomaly indicates that Ce was fixed in a more oxidized environment within a well-drained profile. The hill foot profile JLN-S1 had the highest LREE leaching rate, but also the lowest heavy REE (HREE) leaching rate, which was ascribed to its lowest erosion rate, lowest pH value, and reductive conditions in a more hydromorphic zone down the hill. The releasing rates of REE calculated by a mass balance model at different positions along the catena ranged from 1395 to 14,379 μg m−2y−1. All the observed REE fractionation regimes and weathering rate variations along the hillslope illustrated that topography-regulated hydrologic condition played a critical role in the release and migration of REE during granite weathering.

Overview of breast cancer external beam radiation therapy in Ghana: Towards the establishment of a national standardized treatment guidelines for improved patient care

Background and purposeThis paper reports on results from the foremost national survey on external beam radiation therapy (EBRT) treatment practice at the three radiotherapy (RT) facilities in Ghana. It is to survey the current EBRT treatment protocols and its resources available in the country for breast cancer treatment. Results are intended to form the foundation for future clinical research into developing standardized institutional and/or National breast cancer treatment planning guidelines. This will introduce uniformity into EBRT protocols across the three facilities in the country for their breast cancer patients. Materials and methodsThe survey was conducted with two online-based questionnaires; a general questionnaire that targeted radiation oncology professionals working in the three RT facilities in Ghana and a follow-up specifically for the radiation oncologists. The first survey was rolled out from 21st August 2020 to 31st December 2020. The second survey was conducted from 15th February 2021 to 31st March 2021 after the initial analysis of the responses from the first survey. The first questionnaire had 54 general EBRT breast cancer treatment questions. The second questionnaire had 14 questions focusing on dose fractionation regimens, definition of treatment targets and organs at risk (OAR) delineation. ResultsThe Google web-based questionnaires had in total 11 responses from the targeted radiation oncologists, medical physicists, and radiation therapists working in the three radiotherapy facilities in the country. The facility response rate was 100% for the survey as there were participation from all three RT facilities. CT-based breast planning was considered standard and used in all three facilities. Reference markers to aid patient positioning and target delineations were employed during simulations. Majority of the relevant OAR associated with breast EBRT were very well defined. 3 dimensional conformal radiotherapy (3DCRT) planning with forward-planning field-in-field (FP-FIF) technique has become the preferred planning of choice. From this survey, there were three medical linear accelerators (Linacs) and two Cobalt-60 (Co-60) treatment units used in treating an average of 750 breast cancer patients annually. ConclusionResults from the survey gave an in-depth overview of the current state of EBRT resources available in the treatment and management of breast cancer in Ghana. Minor protocol variations amongst the facilities were observed. However, there were strong consensus amongst the facilities regarding majority of their current existing protocols and possible future techniques/technology implementation.

On the Relationship Between Spatial and Temporary Dose Distribution in Radiotherapy Optimization

The method of mathematical modeling was used to conduct studies aimed at establishing the dependence of optimal dose-fractionation regimens on the spatial dose distribution in tissue and on the tumor location with respect to the spatial dose distribution. The TDF model was used to describe the response of normal tissue to radiation, and the multi-target model was used to describe the reaction of the tumor to radiation. It was shown for the first time that a change in the tumor location relative to the existing spatial dose distribution, as well as a change in the nature of its spatial distribution, led to a change in the parameters of the optimal dose fractionation regimen.

Pneumonitis after Stereotactic Thoracic Radioimmunotherapy with Checkpoint Inhibitors: Exploration of the Dose-Volume-Effect Correlation.

Simple SummaryStereotactic body radiation therapy (SBRT) is widely applied for treatment of early stage lung cancer and pulmonary metastases. Modern immune checkpoint blockade (ICB) is progressively used in cancer treatment. Pneumonitis is a relevant side effect of both thoracic SBRT and ICB. Currently, it remains unclear whether we can presume the same radiation dose–volume–effect correlations and dose constraints for safe application of SBRT + ICB. We present a dose–volume–effect correlation analysis method using pneumonitis contours and dose–volume histograms (DVH). We showed dosimetric differences for pneumonitis volumes between SBRT + ICB and SBRT alone. We found a large extent of pneumonitis, even bilateral and apart from the radiation field for combined SBRT + ICB. We noticed a shift in pneumonitis DVHs towards lower doses and a trend towards decreased areas under the curve (AUC) for SBRT + ICB. This provides a direction for re-evaluation and potential adaptation of lung dose constraints for combined SBRT and ICB.Thoracic stereotactic body radiation therapy (SBRT) is extensively used in combination with immune checkpoint blockade (ICB). While current evidence suggests that the occurrence of pneumonitis as a side effect of both treatments is not enhanced for the combination, the dose–volume correlation remains unclear. We investigate dose–volume–effect correlations for pneumonitis after combined SBRT + ICB. We analyzed patient clinical characteristics and dosimetric data for 42 data sets for thoracic SBRT with ICB treatment (13) and without (29). Dose volumes were converted into 2 Gy equivalent doses (EQD2), allowing for dosimetric comparison of different fractionation regimes. Pneumonitis volumes were delineated and corresponding DVHs were analyzed. We noticed a shift towards lower doses for combined SBRT + ICB treatment, supported by a trend of smaller areas under the curve (AUC) for SBRT+ ICB (median AUC 1337.37 vs. 5799.10, p = 0.317). We present a DVH-based dose–volume–effect correlation method and observed large pneumonitis volumes, even with bilateral extent in the SBRT + ICB group. We conclude that further studies using this method with enhanced statistical power are needed to clarify whether adjustments of the radiation dose constraints are required to better estimate risks of pneumonitis after the combination of SBRT and ICB.