Single-fraction Radiotherapy Research Articles

Comparison of Tumor Control between FLASH and CONV in an Orthotopic Breast Cancer Model

Post-lumpectomy radiotherapy (RT) reduces in-breast tumor recurrence by eradicating residual, occult breast cancer (BC) that may be in the mm size scale. The ability of FLASH-RT to eradicate BC relative to conventional dose rate (CONV) RT is unknown. ∼ 20Gy RT is currently used clinically for single-fraction breast IORT. Determine the effectiveness of FLASH compared to CONV in eradicating small tumors in an orthotopic, syngeneic model of BC using single-fraction 20 or 30Gy RT. Radiation sensitive, mammary tumor cell line Py117 from the transgenic model of the mouse mammary tumor virus promoter driving the polyoma middle T antigen (MMTV- PyMT) efficiently forms non-metastatic, orthotopic tumors in C57BL/6 mice. 106 Py117 cells were injected orthotopically into the left 4th mammary fat pad of C57Bl/6J mice. Radiotherapy was performed with a custom jig that allows for fixed positioning of the target volume (2x2cm radiation field) with 5mm of margin into surrounding tissue. Tumors were irradiated at ∼30mm3 volume or, for comparison, at a range of greater volumes (200-800mm3) with 20 or 30Gy FLASH or CONV with 16-17 MeV electrons. Small 30mm3 tumors regressed until ∼ day 15 after 20Gy single fraction RT then regrew for both FLASH and CONV. 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy with no regrowth up to day 35 post-RT. Larger tumors irradiated with 30Gy regressed until ∼ day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth delay or tumor eradication between FLASH and CONV in any cohort. FLASH was as effective as CONV in controlling growth and eradicating murine BC. Based on other preclinical studies, single-fraction doses between 20 and 30Gy, as well as hypofractioned RT schedules, may identify FLASH doses that achieve comparable tumor control with less toxicity than CONV. Such findings would encourage clinical trials of FLASH in human BC.

Outcomes of omega variant keystone flap in conjunction with single fraction radiotherapy for helical keloids: A comprehensive one-year follow-up study

Achieving esthetically pleasing results for helical keloids can be challenging. This study aims to share the results of a treatment approach for helical keloids, which involves complete excision and reconstruction using an omega variant keystone flap, followed by a single fractional radiotherapy. The current study is a retrospective review of 25 helical keloids in 21 patients from May 2021 to March 2023. All keloid cases were excised entirely. We covered the defect with an omega variant keystone flap followed by a single fraction of 9.5 or 10Gy radiotherapy within 24h after surgery. The mean follow-up period was 12 months. The primary outcome was recorded as recurrence versus non-recurrence. The secondary outcome was scores assessed by the Patient and Observer Scar Assessment Scale. All 25 keloids in 21 patients completed the treatment protocol, with a follow-up interval of 12 months. Of these patients, 100% had successful treatment of their keloids without any keloid recurrence. The postoperative course was uneventful except for one case of early postoperative flap congestion, which was spontaneously healed without any interventions. Scores obtained from the Patient and Observer Scar Assessment Scale showed that pain, itchiness, color, stiffness, thickness, irregularity, vascularity, pigmentation, thickness, relief, and pliability significantly improved. (p<0.001). We successfully reconstructed helical keloids using an omega variant keystone flap after keloid removal followed by 9.5 or 10Gy single fractional radiotherapy without any keloid recurrence in one-year follow-ups.

Comparison of twice weekly palliative RT versus continuous hypofractionated palliative RT for painful bone metastases.

Palliative hypofractionated radiotherapy (RT) is an effective mode of treating painful bone metastasis. While 8 Gy single fraction radiation is often effective for the same, for complicated bone metastases a protracted fractionated regimen is preferred, of which 30 Gy/10#/2weeks or 20 Gy/5#/1 week are the most common worldwide. However such schedules add to the burden of already overburdened radiation treatment facilities in a busy center, wherein alternative logistic favourable schedules with treatment on weekends are preferred. Here we compare the efficacy of a twice weekly schedule to that of standard continuous 20 Gy/5 #/1 week schedule in terms of pain relief, response and quality of life. A prospective non randomized study was undertaken from Jan 2018 to May 2019, wherein eligible patients of complicated bone metastases received palliative radiotherapy of 20 Gy/5#, either continuously for 5 fractions from Monday to Saturday or twice weekly, Saturday and Wednesday, starting on a Saturday over about 2 weeks. Pain relief was assessed by the Visual Analogue Scale (VAS) and FACES pain scale recorded prior to starting palliative RT and at 4 weeks, 3 months and 6 months. Thirteen patients received continuous Hypofractionated RT while 16 received it in a twice weekly schedule. Spine was the most common site receiving palliative Radiation (27/29), while breast cancer was the most common primary (16/29). The demographic and the baseline characteristics were comparable. The mean pain score decline at 4 weeks was 2.56 ± 1.1 and 2.71 ± 0.52 in the 5-day and the two-week schedule, respectively (p = 0.67). A twice weekly schedule over about two weeks was found to be equivalent in pain control and response to the standard fractionated palliative radiation and, thus, can be safely employed in resource constrained, busy radiotherapy centers.

What did COVID-19 pandemics teach us about single-fraction radiotherapy for painful bone metastases-State of the art or undertreatment?

Choosing the optimal treatment approach for patients with painful bone metastases during the COVID-19 pandemic became challenging. A simple technique, single fraction radiotherapy was recommended for these patients usually referring to bone metastases as a single entity, although it is a very heterogeneous group of patients. This study aimed to analyze the response to palliative single fraction radiotherapy in relation to age, performance status, primary tumor, histopathology, and bone localization in the group of patients with painful bone metastases. A clinical, prospective, non-randomized study was conducted at the Institute for Oncology and Radiology of Serbia, which included 64 patients with noncomplicated, painful bone metastases who underwent palliative, pain-relieving radiation therapy with a single tumor dose of 8Gy in a single hospital visit. Response to treatment was patient reported via telephone interview using visual analog scale. The response assessment was based on the international consensus panel of radiation oncologists. In the entire group of patients, 83% responded to radiotherapy. No statistically significant difference was observed in response to therapy, time to reach the maximum response, degree of pain reduction, nor in response duration depending on the patient's age, performance status, the primary origin of the tumor, histopathology, or location of the metastasis (bone) that was irradiated. Regardless of clinical parameters, palliative radiotherapy with a single dose of 8Gy can be considered very effective in quick pain relief in patients with noncomplicated painful bone metastases. Single fraction radiotherapy in a single hospital visit, as well as patient-reported outcome for these patients may be considered favorable beyond Covid pandemics.

Single-Fraction Radiation Therapy for Localized Cutaneous T-Cell Lymphoma

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL). Single-fraction radiation therapy has been used as a skin-targeted therapy to treat localized CTCL lesions. The objective of this study was to investigate the treatment outcomes associated with single-fraction radiation therapy for CTCL. We retrospectively studied the outcomes among patients with CTCL treated with single-fraction radiation therapy at our institution between October 2013 and August 2022. Clinical response (complete response [CR], partial response [PR], or no response [NR]) and retreatment response were evaluated. A total of 242 lesions from 46 patients were analyzed, for an average of 5.3 lesions treated per patient. The majority of lesions presented with a plaque morphology (n=145, 60.0%). All lesions were treated to a dose of 8 Gy in 1 fraction. Median follow-up was 24.6 months (range, 1-88 months). Of the 242 lesions, 36 (14.8%) had an initial PR or NR; all were retreated with the same regimen to the same site at a median interval of 8 weeks. Eighteen of the retreated lesions (50.0%) went on to have a CR. Thus, the overall CR rate for CTCL lesions was 92.6%. No recurrences were noted in the treated areas after achieving CR. Single-fraction radiation therapy to a dose of 8 Gy in 1 fraction to localized areas provided a high rate of complete and durable responses in the affected sites.

Percent of remaining life on palliative radiation treatment: solely a function of fractionation?

This study analyzed the percent of remaining life (PRL) on treatment in patients irradiated for bone metastases. Bone metastases were treated together with other target volumes, if indicated, e.g. a 10-fraction treatment course that included brain and bone metastases. PRL was determined by calculating the time between start and finish of palliative radiotherapy (minimum 1 day in case of a single-fraction regimen) and dividing it by overall survival in days from start of radiotherapy. Different baseline parameters were assessed for association with dichotomized PRL (< 5% vs. ≥ 5%). The retrospective study included 219 patients (287 courses of palliative radiotherapy). After univariate analyses, multi-nominal logistic regression was employed. PRL on treatment ranged from 1-23%. Single-fraction radiotherapy resulted in < 5% PRL on treatment in all cases. All courses with 10 fractions resulted in at least 5% PRL on treatment. Significant associations were found between various baseline parameters and PRL category. With fractionation included in the regression model, 3 parameters retained significant p-values: Karnofsky performance status (KPS), none-bone target volume and fractionation (all with p < 0.001). If analyzed without fractionation, none-bone target volume (p < 0.001), hemoglobin (p < 0.001), KPS (p = 0.01), lack of additional systemic treatment (p = 0.01), and hypercalcemia (p = 0.04) were significant. Fractionation is an easily modifiable factor with high impact on PRL. Patients with KPS < 70 and those treated for additional target types during the same course are at high risk of spending a larger proportion of their remaining life on treatment.

Personalization of Radiation Therapy in the Primary Treatment of Malignant Epidural Spinal Cord Compression (MESCC)

"True" malignant epidural spinal cord compression (MESCC) is used here to describe a lesion compressing of infiltrating the spinal cord associated with neurologic deficits. Radiotherapy alone is the most common treatment, for which several dose-fractionation regimens are available including single-fraction, short-course and longer-course regimens. Since these regimens are similarly effective regarding functional outcomes, patients with poor survival are optimally treated with short-course or even single-fraction radiotherapy. Longer-course radiotherapy results in better local control of malignant epidural spinal cord compression. Since most in-field recurrences occur 6 months or later, local control is particularly important for longer-term survivors who, therefore, should receive longer-course radiotherapy. It is important to estimate survival prior to treatment, which is facilitated by scoring tools. Radiotherapy should be supplemented by corticosteroids, if safely possible. Bisphosphonates and RANK-ligand inhibitors may improve local control. Selected patients can benefit from upfront decompressive surgery. Identification of these patients is facilitated by prognostic instruments considering degree of compression, myelopathy, radio-sensitivity, spinal stability, post-treatment ambulatory status, and patients' performance status and survival prognoses. Many factors including patients' preferences must be considered when designing personalized treatment regimens.

Real World and Public Health Perspectives of Intraoperative Radiotherapy in Early-Stage Breast Cancer: A Multidisciplinary Analysis Beyond the Statistical Facts.

Breast conservation therapy (BCT) (usually a lumpectomy plus radiotherapy (RT)) has become a standard alternative to radical mastectomy in early-stage breast cancers with equal, if not higher, survival rates. The established standard of the RT component of the BCT had been about six weeks of Monday through Friday external beam RT to the whole breast (WBRT). Recent clinical trials have shown that partial breast radiation therapy (PBRT) to the region surrounding the lumpectomy cavity with shorter courses can result in equal local control, survival, and slightly improved cosmetic outcomes. Intraoperative RT (IORT) wherein RT is administered at the time of operation for BCT to the lumpectomy cavity as a single-fraction RT is also considered PBRT. The advantage of IORT is that weeks of RT are avoided. However, the role of IORT as part of BCT has been controversial. The extreme views go from "I will not recommend to anyone" to "I can recommend to all early-stage favorable patients." These divergent views are due to difficulty in interpreting the clinical trial results. There are two modalities of delivering IORT, namely, the use of low-energy 50 kV beams or electron beams. There are several retrospective, prospective, and two randomized clinical trials comparing IORT versus WBRT. Yet, the opinions are divided. In this paper, we try to bring clarity and consensus from a highly broad-based multidisciplinary team approach. The multidisciplinary team included breast surgeons, radiation oncologists, medical physicists, biostatisticians, public health experts, nurse practitioners, and medical oncologists. We show that there is a need to more carefully interpret and differentiate the data based on electron versus low-dose X-ray modalities; the randomized study results have to be extremely carefully dissected from biostatistical points of view; the importance of the involvement of patients and families in the decision making in a very transparent and informed manner needs to be emphasized; and the compromise some women may be willing to accept between 2-4% potential increase in local recurrence (as interpreted by some of the investigators in IORT randomized studies) versus mastectomy. We conclude that, ultimately, the choice should be that of women with detailed facts of the pros and cons of all options being presented to them from the angle of patient/family-focused care. Although the guidelines of various professional societies can be helpful, they are only guidelines. The participation of women in IORT clinical trials is still needed, and as genome-based and omics-based fine-tuning of prognostic fingerprints evolve, the current guidelines need to be revisited. Finally, the use of IORT can help rural, socioeconomically, and infrastructure-deprived populations and geographic regions as the convenience of single-fraction RT and the possibility of breast preservation are likely to encourage more women to choose BCT than mastectomy. This option can also likely lead to more women choosing to get screened for breast cancer, thus enabling the diagnosis of breast cancer at an earlier stage and improving the survival outcomes.

Low-Dose Radiotherapy for Patients with Pneumonia Due to COVID-19: A Single-Institution Prospective Study

Results of the low-dose radiation therapy (LDRT) in patients with pneumonia due to COVID-19 has been presented. Fifteen patients received a single-fraction radiation dose of 1 Gy to the bilateral lungs due to pre-ARDS pneumonia in the course of COVID-19. Follow-up was performed on days 1, 3, 5, 7, 14 after LDRT. Eleven patients (73%) were released up until day 28. Median hospitalization was 20 days; 28-day mortality was 13%. Median O2 saturation improved within 24 h after LDRT in 14/15, with median SpO2 values of 84.5% vs. 87.5% p = 0.016, respectively. At day 14 of hospitalization, 46% did not require oxygen supplementation. Significant decline in CRP and IL-6 was observed within 24 h post LDRT. No organ toxicities were noted. LDRT is feasible, well tolerated and may translate to early clinical recovery in patients with severe pneumonia. Further studies are needed to determine optimal candidate, time and dose of LDRT for COVID-19 patients with pneumonia.

18F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer.

Prostate Specific Membrane Antigen (PSMA) - positron emission tomography (PET) guides metastasis-directed radiotherapy (MDRT) in prostate cancer (PrCa). However, its value as a treatment response assessment tool after MDRT remains unclear. Importantly, there is limited understanding of the potential of radiotherapy (RT) to alter PSMA gene (folate hydrolase 1; FOLH1) expression. We reviewed a series of 11 men with oligo-metastatic PrCa (25 metastasis sites) treated with MDRT before re-staging with 18F-DCFPyL (PSMA) PET upon secondary recurrence. Acute effects of RT on PSMA protein and mRNA levels were examined with qPCR and immunoblotting in human wild-type androgen-sensitive (LNCap), castrate-resistant (22RV1) and castrate-resistant neuroendocrine (PC3 and DU145) PrCa cell lines. Xenograft tumors were analyzed with immunohistochemistry. Further, we examined PSMA expression in untreated and irradiated radio-resistant (RR) 22RV1 (22RV1-RR) and DU145 (DU145-RR) cells and xenografts selected for survival after high-dose RT. The majority of MDRT-treated lesions showed lack of PSMA-PET/CT avidity, suggesting treatment response even after low biological effective dose (BED) MDRT. We observed similar high degree of heterogeneity of PSMA expression in both human specimens and in xenograft tumors. PSMA was highly expressed in LNCap and 22RV1 cells and tumors but not in the neuroendocrine PC3 and DU145 models. Single fraction RT caused detectable reduction in PSMA protein but not in mRNA levels in LNCap cells and did not significantly alter PSMA protein or mRNA levels in tissue culture or xenografts of the other cell lines. However, radio-resistant 22RV1-RR cells and tumors demonstrated marked decrease of PSMA transcript and protein expression over their parental counterparts. PSMA-PET may be a promising tool to assess RT response in oligo-metastatic PrCa. However, future systematic investigation of this concept should recognize the high degree of heterogeneity of PSMA expression within prostate tumors and the risk for loss of PSMA expression in tumor surviving curative courses of RT.

Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases.

LBA492 Purpose: To determine if more patients (pts) with painful liver cancer have improved pain 1 month following radiation therapy (RT), compared to best supportive care (BSC). Methods: This multi-centre, phase III trial randomized pts with painful hepatocellular carcinoma (HCC) or liver metastases (LM) 1:1 to BSC alone or with single fraction RT (8 Gy). Eligible pts had end-stage disease unsuitable for local, regional or systemic therapies, &gt; 4 weeks since chemotherapy or TACE, &gt; 2 weeks since targeted therapy or immunotherapy, and no planned systemic therapy. The primary objective was to determine if the proportion of pts with improved liver cancer pain "intensity at worst" on Brief Pain Inventory (BPI) by ≥2 points from baseline to 1 month was higher following RT vs. BSC alone. Secondary endpoints included proportion of pts 1) alive at 3 months, 2) with improvement ≥2 points in BPI at 1 and 3 months, 3) with a 25% reduction in opioids at 1 month and 4) with improved quality of life (QOL): Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) hepatobiliary subscale (HBS) change score ≥5 and Trial Outcome Index ≥7 at 1 month. Results: Sixty-six pts were randomized, 43 with LM (12 colorectal, 5 breast, 4 pancreas, 3 lung, 19 other), 23 with HCC. 59% had ECOG performance status 2 or 3, 64% Child Pugh (CP) score A vs. 36% CP B or C. The clinical target volume irradiated was the whole liver or near whole liver (median 2013 cc). Forty-two pts (24 on RT and 18 on BSC) completed baseline and 1-month assessments. The average baseline pain at worst score was 7/10. A significant improvement in the primary endpoint, ‘worst’ pain score on BPI, from baseline to 1 month was seen in 67% of pts on RT and 22% on BSC (p = 0.004). The proportion of pts with improved ‘worst’ pain at 1 month, with no increase in opioid use was 21% on RT vs 0% with BSC (p = 0.07). From baseline to 1 month, the proportion of pts with a significant improvement in BPI “pain at its least” was higher for pts on RT vs. BSC (63% vs. 28%, p = 0.03), as was BPI “percentage relief in pain by treatment” (59% vs. 25%, p = 0.04). A sensitivity analysis of all pts, treating those with no 1 month assessment as having ‘no improvement’, found improvements in BPI ‘worst’ pain in 49% of pts on RT and 12% for BSC alone (p = 0.002). Eleven patients on the BSC arm crossed over to receive RT at 1 month. A trend to improvement in FACT HBS post RT vs BSC was seen at 1 month (p = 0.07), with no statistically significant difference in other FACT-Hep subscales. The proportion of pts with grade ≥2 AE (CTCAEv4.0) at day 30 was 58% on RT vs 33% on BSC (p = 0.05). Grade ≥3 AE were uncommon. There was a trend for improved 3 month survival with RT (51% vs. 33% for BSC alone, p = 0.07). Conclusions: Single fraction RT (8 Gy) improves hepatic pain in the majority of patients with end-stage HCC or liver metastases, with a trend to improved survival. This research is funded by the Canadian Cancer Society (Grant #703547). Clinical trial information: NCT02511522 .

Utilization Patterns of Single-Fraction and Short-Course Radiotherapeutic Schedules in the Management of Bone Metastases

Bone metastases are common, occurring in60% to 70% of patients with advanced malignancies. Historically, bone-directed radiation therapy regimens of30 Gyover 10fractions were used. However, prospective randomized data suggestequivalent pain relief with shorter-course regimens. The American Society for Radiation Oncology Choosing Wisely Campaign encourages clinicians to consider shorter-course palliative regimens in patientswith limited prognosis. A retrospective analysis was performedto assess patterns of short-course and single-fraction radiation therapy during the past 5 years. We queried ourelectronic medical record (MOSAIQ) from 2016 to 2020 for patients with bone metastases who received palliativeradiation therapy. Patients receiving >10 fractions or Medicare-approved palliative courses of radiation (30 Gy/10 fractions, 24 Gy/6 fractions, 20 Gy/5 fractions, 8 Gy/1 fraction) were included. Treatment departmentwasdefined as academic (n=2) versus community (n=12). Short-course treatment was defined as <6 fractions, whereas long-course included patients receiving >10 fractions. Patients were subdivided based on age and disease site. Physicians were grouped according to their year of residency completion. Multivariable logistic regression analysis identifiedpredictors of short-course and single-fraction treatment. We identified 1004 patients with 1768 bony metastasesmeeting inclusioncriteria.The spine was the most common site,followed by pelvis/hip, extremity, and other site. Use of short-course treatment increased from 40% in 2016 to 50% in 2020. Single-fraction treatmentincreased from 7% in 2016 to 11% in 2020. Predictors of shorter courses included treatment atacademic centers, more recent treatment, patient age >76 years, and nonspine anatomic site. Predictors of single-fraction treatment included treatment atacademic centers, treating physician residency completion after 2010, patient age >76 years, and treatment to extremity or other site. Rates of short-course and single-fraction bone-directed radiation therapy increased within ourhealth system over time. Treatment receipt atacademic centers was associated with both short-course and single-fraction regimens. Physicians completing residency after 2010 were more likely to deliver single-fraction therapy.

Risk of Myelopathy Following Second Local Treatment after Initial Irradiation of Spine Metastasis.

Metastatic lesions of the spine occur in up to 40% of cancer patients and are a frequent source of pain and neurologic deficit due to cord compression. Palliative radiotherapy is the main first-intent local treatment in the form of single-fraction radiotherapy or fractionated courses. Reirradiation is a viable option for inoperable patients where spinal decompression is needed but with an increased risk of radiation-induced myelopathy (RM) and subsequent neurologic damage. This review summarizes reported data on local treatment options after initial irradiation in patients with relapsed spine metastasis and key dosimetric correlations between the risk of spinal cord injury and reirradiation technique, total dose, and time between treatments. The Linear Quadratic (LQ) model was used to convert all the published doses into biologically effective doses and normalize them to EQD2. For 3D radiotherapy, authors used cumulative doses from 55.2 Gy2/2 to 65.5 Gy2/2 EQD2 with no cases of RM mentioned. We found little evidence of RM after SBRT in the papers that met our criteria of inclusion, usually at the median reported dose to critical neural tissue around 93.5 Gy2/2. There is a lack of consistency in reporting the spinal cord dose, which leads to difficulty in pooling data.

Current Radiotherapy Concepts Regarding Brain and Bone Metastases in Centers Participating in the German-Danish Interreg-Project TreaT.

Radiotherapy regimens for brain or bone metastases vary substantially. This study compared regimens utilized in Northern Germany and Denmark. Three centers participating in the Interreg-Project TreaT completed questionnaires regarding preferred radiotherapy regimens for brain or bone metastases. Brain metastases: In poor-prognosis patients, all centers prefer short-course whole-brain irradiation (WBI) for multiple metastases. For oligometastatic disease, two centers prefer WBI, one center fractionated stereotactic radiotherapy (FSRT). For single lesions, all centers use FSRT. In intermediate- or favorable-prognosis patients, longer-course WBI is preferred for multiple lesions, sometimes with simultaneous-integrated boost. For oligo-metastasis, regimens vary. FSRT is preferred for single lesions. Bone metastases: For poor-prognosis patients, single-fraction radiotherapy is used for uncomplicated metastases and short-course radiotherapy for (impending) fractures, large soft-tissue components, and spinal cord compression. Multi-fraction regimens are preferred for intermediate-prognosis and longer-course regimens for favorable-prognosis patients. Regimens are relatively similar for bone metastases, single and multiple brain lesions, but vary considerably for few brain metastases. Further cross-border collaboration is required to provide more uniform and optimized treatment standards.

Phase Ib/II study of nivolumab combined with palliative radiation therapy for bone metastasis in patients with HER2-negative metastatic breast cancer

Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4–29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23–58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1–6.1 months) and 2.0 months (95% CI 1.2–3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted.Trial registration number and date of registration UMIN: UMIN000026046, February 8, 2017; ClinicalTrials.gov: NCT03430479, February 13, 2018; Date of the first registration: June 22, 2017.

Targeting Cellular Metabolism With CPI-613 Sensitizes Pancreatic Cancer Cells to Radiation Therapy

PurposeLocal tumor progression is a cause of significant morbidity and mortality in patients with pancreatic ductal adenocarcinoma (PDAC) with surgically unresectable disease. Novel and effective approaches to accomplish durable local control are urgently needed. We tested whether CPI-613 (devimistat), a first-in-class investigational small molecule inhibitor of mitochondrial metabolism, was capable of altering cancer cell energy metabolism and sensitizing PDAC cells to radiation therapy (RT). Methods and MaterialsThe effect of a combined treatment of RT with CPI-613 on the viability of, clonogenic potential of, and cell death induction in PDAC cells (MiaPaCa-2 and Panc-1) was determined using a trypan blue dye exclusion assay, a colony formation assay, and a 7–amino-actinomycin D assay, respectively. The synergistic effects of CPI-613-RT and chemotherapeutic agents (gemcitabine or 5-fluorouracil) were measured in MiaPaCa-2 cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and spheroid formation assay. Changes in energy metabolism were determined by profiling metabolites treated with either RT, CPI-613, or both using liquid chromatography-mass spectrometry. ResultsThis study demonstrates that a combination of single-fraction RT (2 and 10 Gy) with CPI-613 significantly inhibits PDAC cell growth compared with RT alone. Molecular analysis revealed inhibition of α-ketoglutarate dehydrogenase at the protein level. In addition, we demonstrate enhanced cell death of PDAC cells when treated with RT-CPI-613 combination. Targeted metabolomic analysis on PDAC cells post–CPI-613-RT treatment revealed alterations in key mitochondrial metabolites, with broader target engagement by the combination treatment, indicating the sensitization of CPI-613–treated PDAC cells to RT. Furthermore, a combination treatment of CPI-613 with either gemcitabine or 5-fluorouracil in the presence of 2 Gy RT synergistically inhibits PDAC cell proliferation. ConclusionsOur results support a novel combination of CPI-613-RT that warrants further preclinical and early-phase clinical investigations. A phase 1 trial designed to identify the maximum tolerated dose of CPI-613 in combination with chemo-RT in patients with PDAC was recently initiated (NCT05325281).

The Impact of Chemoradiotherapy on Biophysical Properties of Glioblastoma Utilizing a Novel Murine Model

<h3>Purpose/Objective(s)</h3> Glioblastoma, historically viewed as a single disease entity, is now known to be composed of various subtypes. Here, we present our work evaluating the effects of chemoradiotherapy on cellular biophysical processes using a novel murine model of glioblastoma developed by our group. <h3>Materials/Methods</h3> Primary tumor cell lines were established from a murine glioma model generated from a synthetic DNA transposon system delivered oncogenic drivers SV40-LgTA and either NRASV12 or PDGFB. We have previously shown these cell lines, termed NRAS and PDGF, respectively, recapitulate the mesenchymal and proneural tumor subtypes. Treatment was administered with temozolomide (TMZ) to a maximum of 100µM, single fraction radiation therapy (RT) to a maximum of 10 Gy, or both. Cells were stained with Hoechst dye, imaged with an epifluorescence microscope with 10X objective lens, and counted with an image segmentation algorithm daily for 4 days to estimate cell survival and proliferation. On post-treatment day 4, surviving cells were plated on Matrigel coated 9.3kPa polyacrylamide gel and imaged with an inverted, transmitted light microscope with 10X objective lens every 5 minutes for 4 hours. Single cell mean squared displacement (MSD) was measured from time lapse images via an image segmentation algorithm. The random motility coefficient (µ) was calculated by the relationship MSD(t) = 4µt, where t is time. Data was compared via the Kruskal-Wallis test with Bonferroni correction for multiple comparisons when appropriate. <h3>Results</h3> There was no significant difference in cellular death or proliferation between treatment and control arms for the PDGF cell lines. In the NRAS cell lines, TMZ alone did not induce cell death while RT (P < 0.01) and combined modality therapy (P < 0.01) yielded cellular killing in a dose dependent manner. Furthermore, RT-treated NRAS cells proliferated more slowly than non-treated cells (0.05 vs. 0.20 hr-1, P=0.04). Control NRAS cell lines migrated faster than their PDGF counterparts at baseline (3.82 vs. 0.73 µm2/hr, P<1E-5). Within each cell line, the use of combined modality therapy significantly reduced cellular motility (PDGF: 0.73 vs. 0.21 µm2/hr, P=0.008; NRAS: 0.65 vs. 3.82 µm2/hr, P<1E-5). RT monotherapy additionally reduced motility in NRAS cell lines (1.07 vs. 3.82 µm2/hr, P<1E-5) while no difference was observed in PDGF cells. TMZ monotherapy did not affect motility within either cell line. <h3>Conclusion</h3> We evaluated biophysical properties of a novel murine glioma model utilizing oncogenic drivers overexpressing NRASV12 or PDGFB which we have previously shown recapitulates the mesenchymal and proneural subtypes of human glioblastoma, respectively. Here, we observed phenotypic differences in cellular migration following RT and TMZ regimens which could have subtype-specific ramifications for radiotherapy dose and target volume delineation.

Environmental Sustainability in Radiation Oncology: A Scoping Review

<h3>Purpose/Objective(s)</h3> In the United States, the healthcare industry accounts for roughly 10% of greenhouse gas emissions. In recent years, interest in environmental sustainability in relation to the healthcare sector has increased. To date, little research has been conducted to assess the relationship of radiation therapy and its impact on the environment. This scoping review aims to examine and thematically organize literature regarding this subject. <h3>Materials/Methods</h3> An evaluation of evidence was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols extension for Scoping Reviews (PRISMA-ScR). Manuscripts were included that involved environmental sustainability and radiation therapy. Databases Web of Science, MEDLINE, and Scopus were queried, along with gray literature, to identify relevant publications between 1975 and 2022. Data was qualitatively analyzed and categorized. <h3>Results</h3> Of 61 articles identified, 7 met inclusion criteria, including: 5 observational studies, 1 randomized control trial and 1 case report. In relation to radiation therapy, environmental sustainability was classified by: 1) direct carbon emission/energy consumption for radiation therapy delivery; or 2) indirect carbon emission/energy consumption from sources such as patient travel, material utilization and resource lifecycle. Notably, 5 major radiation therapy companies consistently reported material, water, and energy consumption with 3 groups further differentiating between renewable and nonrenewable energy sources. From 2018 to 2021, radiation therapy companies reported decreases in total carbon emissions of 8% to 15% annually, with individual companies' global emissions ranging from 464,917 tons CO₂e to 781,865 tons CO₂e. One randomized control trial was identified which reported that single fraction radiation therapy was associated with decreased CO₂ vehicle emissions compared to conventionally fractionated radiation therapy due to minimizing treatment-related travel. Regarding direct energy usage, one case study demonstrated that with a new sustainably oriented system vs a standard linear accelerator, energy consumption decreased 70% from 4,500 kWh per month to 1,200 kWh per month, while the number of fractions delivered increased from 497 to 610. <h3>Conclusion</h3> This scoping review identified recent technologic advancements from the supplier side, with increasing emphasis on minimizing directly and indirectly related carbon emissions and energy consumption. Several gaps in the literature were identified including comparison of various treatment modalities such as single vs multifraction treatment and photon vs proton vs carbon therapy energy requirements. Further research is needed to elucidate avenues to minimize the environmental impact of radiation therapy while maintaining the highest quality patient care.

Hypofractionated Two Week Short-Course Radiotherapy vs. Monthly Single Fraction Palliative Pelvic Radiation in Advanced Gynecologic Cancers

<h3>Purpose/Objective(s)</h3> This prospective study compares the effectiveness of hypo fractionated two-week short course radiotherapy versus monthly single fraction radiotherapy, as palliative radiotherapy in advanced gynecologic cancers. The primary end point was subjective response in symptoms and secondary end points were the impact on quality of life, objective response rate and treatment related toxicity. <h3>Materials/Methods</h3> Fifty patients with advanced or metastatic cancer of the cervix, endometrium, vulva and vagina with significant pelvic symptoms and unfit for curative treatment were enrolled in the study. Palliative radiotherapy was planned using conventional fluoroscopic simulator with standard pelvic radiation portals. Radiotherapy was delivered using a Co-60 unit or Linear Accelerator with 6MV photons. Patients randomized to two-week radiotherapy arm received a dose of 30Gy in 10 fractions over two weeks and those in the single fraction arm received 8 Gy single fraction, up to 3 fractions at monthly interval. The decision of second and third fraction was based on symptom relief and tumor response. Disease symptoms and Quality of life were assessed using the ESAS-r and FACT questionnaires respectively. Toxicity was assessed using the CTCAE (version 5) and WHO subjective treatment response assessment was done. <h3>Results</h3> Of the 25 patients recruited in each arm, all patients completed treatment in the 30Gy/10 fractions arm. In the single fraction arm, 6 (24%) had good symptom control after one fraction, and 8 (32%) required 2 fractions and 11 patients (44%) required three fractions. The median follow- up period was 7.5 months. Compared to baseline, there was a significant improvement in the symptom scores at 1, 3 and 6 months in both the arms. There was no significant difference in the symptom scores between the two treatment arms. The overall symptomatic response rates in the 30Gy/10# and SFRT arm were more than 80%for pelvic pain, 96% for vaginal bleeding and more than 80%for vaginal discharge. When compared with baseline, Quality of life scores at 1, 3 and 6 months showed significant improvement in all domains in both the arms. The emotional and physical well-being scores at 3 months were significantly better (p=0.02 and 0.04) in the 30Gy/10# arm compared to the SFRT arm. There was no difference in the treatment toxicities between both the arms. At last follow-up, 50% had stable disease, 26% had progressive disease and 24% had partial response to treatment. There was no difference in the response rates between both the arms <h3>Conclusion</h3> Palliative Pelvic Radiation provides significant symptomatic relief and improves the Quality of life of patients with Advanced Gynecologic cancers. Single fraction palliative radiation is comparable to two-week hypo-fractionated radiotherapy with comparable symptom control, toxicities, and improvement in quality of life. The improved emotional and physical wellbeing scores in the two-week radiotherapy arm could be due to the psychological effect of a longer treatment.

Optimizing Lung SBRT Dose while Accounting for Histology Ensures Optimal Local Control for Inoperable Stage I Non-Small Cell Lung Cancer: Can Higher Biologically Equivalent Dose Overcome Size and SUV?

<h3>Purpose/Objective(s)</h3> Retrospective studies suggest that increasing tumor size, PET avidity and squamous histology unfavorably impact local failure (LF) after lung SBRT. We sought to characterize the interaction of SBRT dose with these variables known to be associated with LF. <h3>Materials/Methods</h3> We identified 1,573 consecutive patients treated with definitive intent SBRT for stage I NSCLC from 2003-2020 from an IRB-approved institutional prospective registry. We utilized competing risk regression, with death as a competing event, to identify patient, tumor and treatment factors associated with the endpoints LFand any failure (AF), and Cox proportional hazards regression for overall survival (OS). <h3>Results</h3> Median tumor size was 2.2 cm and PET SUV 7.5. Histology was adenocarcinoma in 30.6%, squamous cell in 27.8%, NSCLC NOS in 7.3%, non-diagnostic in 9.7% and unbiopsied in 24.3%. 52.3% of patients were female; 5% never smokers, 72.7% former smokers, and 22.3% active smokers. 64% completed mediastinal staging and 93.9% were medically inoperable. Median Charlson score was 6, and median age 74.7 years. SBRT regimen was 30/1 in 5%, 34/1 in 21%, 48-50 Gy/4-5 in 46%, 54-60/3 in 24% and 50-60 Gy/8-10fx in 3%. With a median follow-up of 22.9 months 7.9% of patients had LF and 31.2% had AF 31.2%. Median OS was 35.4 months. On univariate analysis, squamous histology had a higher risk for LF vs. adenocarcinoma (HR=2.15, p=0.001). There was no difference in LF for NSCLC NOS (HR= 0.85, p=0.71) and un-biopsied patients (HR= 1.23, p=0.40) vs. adenocarcinoma. Other factors associated with increased risk of LF were tumor size (p<0.0001), metabolic activity (p<0.0001), and lower BED radiation dose (48-50 Gy/4-5 fx, BED 100-105, HR=3.56, p<0.0001). Single fraction radiation (BED 149.6) had similar LF compared to 54-60 Gy/3 fx (BED 150-180). On multivariable analysis, tumor size and metabolic activity were no longer statistically significant, leaving squamous histology (HR=1.92, p=0.0086) and lower BED radiation (48-50 Gy/4-5 fx, HR=3.07, p=0.002) as significant correlates. On multivariable analysis for AF, tumor size and metabolic activity were significantly associated with AF, while SBRT dose and squamous histology were not statistically significant. A broad range of correlates with OS were identified (age, gender, ethnicity, KPS, Charlson score, hemoglobin level, tumor size, PET SUV, histology, and SBRT dose). <h3>Conclusion</h3> While tumor size, PET avidity, squamous histology and SBRT dose were univariate correlates for LF, only squamous histology and SBRT dose remained significant on multivariate analysis. Squamous histology appears to be an independent driver of LF. Higher SBRT dose (54-60 Gy/3fx, 34 Gy/1 fx, BED >149) may overcome other correlates to LF (size, SUV), though these remain as the strongest correlates to distant recurrence.