Optimal Fractionation Schedule Research Articles

Palliative Thoracic Radiotherapy in the Era of Modern Cancer Care for NSCLC.

Palliative thoracic radiotherapy provides rapid and effective symptom relief in approximately two-thirds of NSCLC patients treated. In patients with poor performance status, the degree of palliation appears unrelated to the radiation dose or fractionation schedule. Conversely, in patients with good performance status, higher radiation doses administered over longer periods have shown modest survival benefits. These findings stem from studies conducted before the advent of immunotherapy and targeted therapy in clinical practice. Currently, there are no large prospective studies specifically dedicated to palliative radiotherapy conducted in this new treatment era. Modern radiotherapy technologies are now widely available and are increasingly used for palliative purposes in selected patients, reflecting the expanded array of therapeutic options for disseminated NSCLC and improved prognosis. Some traditional tenets of palliative thoracic radiotherapy, such as the improvement of overall survival with a protracted radiation schedule and the use of simple, cost-effective radiation techniques for palliative purposes, may no longer hold true for patients receiving immunotherapy or targeted therapy. The application of IMRT or SBRT in the context of palliative radiotherapy for NSCLC is not yet sufficiently explored, and this is addressed in this review. Moreover, new risks associated with combining palliative radiotherapy with these systemic treatments are being explored and are discussed within the context of palliative care. The optimal timing, doses, fractionation schedules, and treatment volumes for radiotherapy combined with immunotherapy or targeted therapy are currently subjects of investigation. In emergencies, radiotherapy should be used as a life-saving measure without delay. However, for other indications of palliative thoracic radiotherapy, decisions regarding doses, timing relative to systemic treatments, and treatment volumes should be made in a multidisciplinary context, considering the patient's prognosis, anticipated outcomes, and access to potentially effective treatments. We still lack robust data from prospective studies on this matter. This review examines and discusses available evidence on the use of palliative thoracic radiotherapy within the framework of modern treatment strategies for NSCLC.

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer: Efficacy results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy: A 9-year update

Background and PurposeHigh dose-rate (HDR) brachytherapy as a monotherapy is an accepted treatment for localized prostate cancer, but the optimal dose and fractionation schedule remain unknown. We report on the efficacy of a randomized Phase II trial comparing HDR monotherapy delivered as 27 Gy in 2 fractions vs. 19 Gy in 1 fraction with a median follow-up of 9 years. Materials and MethodsEnrolled patients had low or intermediate-risk disease, <60 cc prostate volume and no androgen deprivation use. Patients were randomized to 27 Gy in 2 fractions delivered one week apart vs a single fraction of 19 Gy. Results170 patients were randomized: median age 65 years, median follow-up 107 months and median baseline PSA 6.35 ng/ml. NCCN risk categories comprised low (19 %), favourable (51 %), and unfavourable intermediate risk (30 %). The median PSA at 8 years was 0.08 ng/ml in the 2-fraction arm vs. 0.89 ng/ml in the single-fraction arm. The cumulative incidence of local failure at 8 years was 11.2 % in the 2-fraction arm vs. 35.9 % in the single-fraction arm (p < 0.001). The incidence of distant failure at 8 years was 3.8 % in the 2-fraction arm and 2.5 % in the single-fraction arm (p = 0.6). ConclusionsHDR monotherapy delivered in two fractions of 13.5 Gy demonstrated a persistent cancer control rate at 8 years and was well-tolerated. Single-fraction monotherapy yielded poor oncologic control and is not recommended. These findings contribute to the ongoing discourse on optimal HDR monotherapy strategies for low and intermediate-risk prostate cancer.

Safety and early efficacy of involved-field SBRT for nodal oligo-recurrent prostate cancer.

Following treatment for localized prostate cancer, a subset of men will develop recurrent disease in the abdominopelvic nodes. For radiation therapy (RT), the optimal treatment volume, fractionation schedule, and dose remain unanswered questions. We report early outcomes for patients treated with involved-field stereotactic body radiation therapy (SBRT) (IF-SBRT) for nodal oligo-recurrent (NOR) prostate cancer. Between January 2018 and October 2023, 67 patients with a median age of 75 with NOR prostate cancer treated with 74 courses of IF-SBRT at Georgetown were eligible for this analysis. NOR was defined as any volume of disease that could be safely treated within an IF. All patients were treated with five-fraction IF-SBRT (27.5-35 Gy). The IF treatment volume was defined as the nodal basin containing the gross disease as well as the immediately adjacent basins. Disease progression was defined as a prostate-specific antigen (PSA) rise above the pretreatment baseline or initiation of a second treatment. Local control and progression-free survival were calculated using the Kaplan-Meier method. Detection of pre-SBRT NOR was ascertained by prostate-specific membrane antigen (PSMA) (38%), fluciclovine (50%), or MRI/CT (12%). Median follow-up was 50 months (1-262). The median pre-salvage PSA was 6.5 ng/mL (range, 0.1-335). The median number of involved nodes was 3 (range, 1-16). The local control at 1 and 2 years was 98% and 93%, respectively. The 1- and 2-year progression-free survival was 78% and 50%, respectively. Twenty percent of treatment courses were followed by acute Grade 2 gastrointestinal (GI) toxicity: diarrhea (9%) and/or nausea (14%). Two patients (3%) experienced late Grade 2 nausea. On univariate analysis, measures of disease volume such as hormone sensitivity (p = 0.03), increasing involved node number (p = 0.008), and abdominal treatment (p = 0.03) were significantly associated with GI toxicity. With the widespread adoption of PSMA agents, NORs are likely to increase. The optimal combination of local and systemic therapy in this population is unknown. With a favorable toxicity profile, IF-SBRT represents a safe and convenient local therapy treatment option for an elderly patient population. Patient- and treatment-related factors such as a large number of involved nodes and/or abdominal treatment may be associated with an increased risk of GI toxicity.

Proliferation Saturation Index to Simulate Adaptive Radiation Fractionation in HPV-Associated Oropharyngeal Cancer

In current clinical practice for fractionated radiotherapy (RT) patients receive a fixed fractionation protocol throughout radiation course. Radiation oncology has not yet moved toward adaptive fractionation to change RT fractionation based on individual patients' response dynamics. We have previously introduced a novel mathematical and imaging biomarker, proliferation saturation index (PSI), to simulate and evaluate tumor volume dynamics during therapy. Robust tumor volume reduction was associated with lower PSI, and PSI has been utilized to select fractionation schedules for the first mathematical model informed clinical trial. Here we simulate the possibility of adapting the selection of RT fractionation on a week-by-week basis by utilizing a dynamic weekly estimation of PSI. We generated a cohort of in silico patients by sampling from distributions of PSI, radiosensitivity, and growth rate parameters. These distributions were by pre-treatment and on-treatment tumor volume dynamics from a prospective clinical trial (NCT03656133), where 49 HPV+ OPC patients were treated with either 2 Gy daily fractions up to a total of 70 Gy if PS<0.75, or hyperfractionation at 1.2 Gy b.i.d. up to a total of 66 Gy for patients with PSI ≥ 0.75. We then simulated standard (2 Gy q.d.) and hyperfractionated (1.2 Gy b.i.d) for 1-8 weeks of RT to build a library of response dynamics for the different parameter combinations and treatment durations. This library was then used to estimate optimal adaptive fractionation schedules for the in silico patients that maximized tumor volume reduction and minimized total RT dose. We found that PSI evolved towards lower values (i.e., higher proliferative fractions) over the fractionation RT treatment course. For patients that began treatment with standard fractionation, no adaption was found to be superior to uniform fractionation. For selected patients who began treatment with hyperfractionation, however, the optimal fractionation schedule included a period of upfront hyperfractionated RT followed by a switch to standard fractionation at different times during their treatment course. The results of this study suggest that in addition to selecting the best initial fractionation schedule, a novel approach to personalize RT for OPC patients may include adapting the fractionation based on early treatment response dynamics. These results motivate validation in prospective clinical trials.

Palliative Radiotherapy for Haemostasis in Malignancy: a Systematic Review

AimsPalliative radiotherapy is commonly used to achieve haemostasis for malignancy-induced haemorrhages. Our study aimed to examine the efficacy of palliative radiotherapy in the control of haemorrhages caused by various types of malignancy. Materials and methodsA systematic review of the literature was conducted to determine the level of evidence for the use of palliative radiotherapy in achieving haemostasis. Searches of the Medline, Embase and Cochrane databases were completed for studies published between January 1947 and May 2017. Studies that reported either a qualitative or a quantitative effect of radiotherapy were selected for inclusion during the review process. ResultsIn total, 836 abstracts were screened; 13 prospective and 45 retrospective studies met the criteria for inclusion in the review. Selected studies were sorted based on the underlying tumour type to provide readers the opportunity to compare dose and fractionation schedules. Significant variations in reporting of outcomes and low total patient numbers did not allow for a quantitative analysis to be carried out. A higher median dose and a hypofractionated schedule seem to provide numerically higher rates of control based on the available data. ConclusionsPalliative radiotherapy is useful in the management of bleeding related to advanced and incurable malignancies. Brachytherapy seems to be effective in haemostasis of certain malignancies, especially that of gynaecological origin. Treatment should be tailored to individual patient situations given the palliative goals of any such therapy. Further prospective studies could help to delineate optimal dose and fractionation schedules.

Utilization and Survival Impact of Hypofractionated Radiotherapy in Stage I Non-small Cell Lung Cancer.

The optimal fractionation schedule in unresected stage I non-small cell lung cancer (NSCLC) unsuitable for stereotactic body radiation therapy is unclear. Given the lack of comparative data regarding nonstereotactic body radiation therapy schemas, we compared overall survival (OS) with hypofractionated radiotherapy (HFRT) versus conventionally fractionated radiotherapy (CFRT) and examined the OS impact of different HFRT doses. This retrospective analysis included 2159 patients from the National Cancer Database diagnosed with stage I (cT1-2aN0M0) NSCLC between 2008 and 2016. Patients underwent CFRT (70≤BED10 [biologically effective dose] <100 Gy10 in ≥30 fractions), low-dose HFRT (LD-HFRT; 70≤BED10 [assuming α/β=10] <100 Gy10 in 11 to 24 fractions), or high-dose HFRT (HD-HFRT; 100≤BED10 ≤120 Gy10 in 6 to 10 fractions). Patients who received surgery, chemotherapy, or immunotherapy were excluded. We compared CFRT versus all HFRT, and separately CFRT versus LD-HFRT and CFRT versus HD-HFRT. OS was evaluated with the Kaplan-Meier estimator, log-rank test, and Cox regression. A total of 63.2% of patients underwent CFRT, 23.5% LD-HFRT, and 13.3% HD-HFRT. OS was significantly longer with HFRT versus CFRT on univariable (28.2 mo [95% CI, 25.6-31.7] vs 26.4 mo [25.0-27.9]; log-rank=0.0025) but not multivariable analysis (MVA; hazard ratio [HR] 0.90; P=0.062). MVA yielded no significant difference in OS between CFRT and LD-HFRT (HR 0.96, P=0.53). OS was significantly longer with HD-HFRT versus CFRT on MVA (HR, 0.75; P=0.003). However, on sensitivity analysis using different multivariable modeling techniques, this did not retain statistical significance (HR, 0.83; P=0.12). For stage I NSCLC, HFRT does not show a robust OS benefit compared with CFRT but may be preferred given the convenience and lower costs.

Radiosurgery fractionation and post-treatment hemorrhage development for intact melanoma brain metastases.

To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development. A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BED2.5). Statistical analysis was performed using mixed effect logistic regression for post-treatment HA and Cox frailty modeling for local control (LC). The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BED2.5 was observed in lesions developing HA compared to no HA (238.3Gy vs. 211.4Gy; p = 0.022). 12-month LC was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment HA, respectively, with no local failure events observed within 12months for non-hemorrhagic lesions (p < 0.001). We found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED2.5, which was significantly higher for single fraction treatments within our cohort. The presence of lesion HA, either pre- or post-treatment, was indicative of inferior LC. Further investigations of optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

Dose-Escalated 2-Fraction Spine Stereotactic Body Radiation Therapy: 28 Gy Versus 24 Gy in 2 Daily Fractions

Stereotactic body radiation therapy (SBRT) for spine metastases improves pain response rates compared with conventional external beam radiation therapy; however, the optimal fractionation schedule is unclear. We report local control and toxicity outcomes after dose-escalated 2-fraction spine SBRT. A prospectively maintained institutional database of over 600 patients and 1400 vertebral segments treated with spine SBRT was reviewed to identify those prescribed 28 or 24 Gy in 2 daily fractions. The primary endpoint was magnetic resonance imaging based local failure (LF), and secondary endpoints included overall survival and vertebral compression fracture (VCF). A total of947 treated vertebral segments in 482 patients were identified, of which 301 segments in 159 patients received 28 Gy, and 646 segments in 323 patients received 24 Gy in 2 fractions. Median follow-up per patient was 23.5 months, and median overall survival was 49.1 months. In the 28 Gy cohort, the 6-, 12-, and 24-month cumulative incidences of LF were 3.5%, 5.4%, and 11.1%, respectively, versus 6.0%, 12.5%, and 17.6% in the 24 Gy cohort, respectively (P=.008). On multivariable analysis, 24 Gy (hazard ratio [HR], 1.525; 95% confidence interval, 1.039-2.238; P=.031), paraspinal disease extension (HR, 1.422; 95% confidence interval, 1.010-2.002; P=.044), and epidural extension in either radioresistant or radiosensitive histologies (HR, 2.117 and 1.227, respectively; P=.003) were prognostic for higher rates of LF. Risk of VCF was 5.5%, 7.6%, and 10.7% at 6, 12, and 24 months, respectively, and was similar between cohorts (P=.573). Spinal malalignment (P < .001), baseline VCF (P=.003), junctional spine location (P=.030), and greater minimum dose to 90% of planning target volume were prognostic for higher rates of VCF. Dose escalation to 28 Gy in 2 daily fractions was associated with improved local control without increasing the risk of VCF. The 2-year local control rates are consistent with those predicted by the HypofractionatedTreatment Effects in the Clinic spine tumor control probability model, and these data will inform a proposed dose escalation randomized trial.

Dose-Escalated Two-Fraction Spine Stereotactic Body Radiotherapy: 28 Gy vs. 24 Gy in 2 Daily Fractions

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) for spine metastases improves pain response rates and local control compared to conventional external beam radiotherapy, however, the optimal fractionation schedule is unclear. We report local control and toxicity outcomes after dose-escalated two-fraction spine SBRT. <h3>Materials/Methods</h3> A prospectively maintained institutional database of over 600 patients and 1400 vertebral segments treated with spine SBRT, using an established treatment technique, was reviewed to identify those treated with 28 Gy or 24 Gy in two daily fractions. The primary endpoint was MRI-based local failure (LF), and secondary endpoints included overall survival (OS) and vertebral compression fracture (VCF). <h3>Results</h3> A total of 947 treated vertebral segments in 482 patients were identified, of which 159 patients (301 segments, 31.8%) received 28 Gy and 323 patients (646 segments, 68.2%) received 24 Gy in 2 fractions. Median follow-up was 23.5 months and median OS was 49.1 months. In the 28 Gy cohort, the 6-, 12-, and 24-month cumulative incidences of local failure were 3.5%, 5.4% and 11.1%, respectively, vs. 6.0%, 12.5% and 17.6% in the 24 Gy cohort, respectively (p=0.0075). On multivariable analysis, 24 Gy (HR: 1.572, 95%CI: 1.08-2.30, p=0.0196), epidural disease (HR: 1.522, 95%CI: 1.10-2.10, p=0.0108), and paraspinal extension (HR: 1.517, 95%CI: 1.08-2.12, p=0.0151) predicted for greater rates of local failure. Risk of VCF was 5.5%, 7.6% and 10.7% at 6-, 12- and 24-months, respectively, and similar between the two cohorts (p=0.573). Spinal malalignment (p<0.001), baseline vertebral body collapse (p=0.0027), junctional spine location (p=0.0296), and a greater PTVD90 predicted for greater rates of VCF. <h3>Conclusion</h3> 28 Gy in 2 daily fractions was associated with improved local control without increasing the risk of VCF, and the 2-year local control rates fit the HYTEC spine tumor control probability model.

Single-Fraction vs. Fractionated Radiosurgery and the Development of Post-Treatment Hemorrhage for Intact Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> To assess whether intracranial stereotactic radiotherapy fractionation is associated with increased risk of post-treatment lesional hemorrhage in patients with intact melanoma brain metastases (MBM). <h3>Materials/Methods</h3> A single institution retrospective review was performed of patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 to 2021. The presence of lesional hemorrhage was determined by multi-disciplinary neuroradiology review of magnetic resonance imaging (MRI). Dosimetric variables were reported as biologically effective doses using an estimated α/β ratio of 2.5 (BED_2.5) for melanoma to permit comparison across varying fractionation schedules. The effect of fractionation and additional prognostic factors on the rate of post-treatment development of hemorrhage was statistically analyzed using logistic regression with random effects to account for interactions between lesions of the same patient. A Cox model was used for local control (LC) with a frailty term to account for dependence between lesions. <h3>Results</h3> The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Evidence of hemorrhage prior to treatment was demonstrated in 69 of 226 metastases (30.5%). For lesions without signs of prior hemorrhage, 65 of 157 (41.4%) demonstrated evidence of hemorrhage after radiosurgical treatment. 63 of 133 lesions (47.4%) receiving single-fraction SRS demonstrated evidence of post-treatment hemorrhage versus 2 of 24 lesions (8.3%) treated with fSRT (<i>p=0.01</i>). Treatment factors including lesion size, prescription isodose line, as well as receipt of corticosteroids, targeted, or immune therapy were not predictive of hemorrhage occurrence. A larger maximum BED_2.5 was observed in lesions developing hemorrhage compared to no hemorrhage (mean 238.3 Gy vs. 211.4 Gy; <i>p=0.022</i>). LC at twelve-months was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment hemorrhage, respectively, with no local failure events observed in non-hemorrhagic lesions (<i>p=<0.001</i>). <h3>Conclusion</h3> Intact MBM without prior evidence of hemorrhage receiving single-fraction SRS were associated with an increased incidence of post-treatment hemorrhage when compared to those treated with fractionated stereotactic radiotherapy. The presence of lesion hemorrhage, either pre- or post-treatment, was associated with inferior local control. Post-treatment hemorrhage was correlated with a larger maximum BED_2.5. Further investigations of the clinical impact of lesional hemorrhage, factors influencing lesion control, as well as optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

Hypofractionated or Conventionally Fractionated Adjuvant Radiotherapy After Regional Lymph Node Dissection for High-Risk Stage III Melanoma

AimsAdjuvant radiotherapy can be beneficial after regional lymph node dissection for high-risk stage III melanoma, as it has been shown to reduce the risk of recurrence in the node field. However, the optimal fractionation schedule is unknown and both hypofractionated and conventionally fractionated adjuvant radiotherapy are used. The present study examined the oncological outcomes of these two approaches in patients treated in an era before effective systemic immunotherapy became available. Materials and methodsThis retrospective cohort study involved 335 patients with stage III melanoma who received adjuvant radiotherapy after therapeutic regional lymph node dissection for metastatic melanoma between 1990 and 2011. Information on tumour characteristics, radiotherapy doses and fractionation schedules and patient outcomes was retrieved from the institution's database and patients' medical records. ResultsHypofractionated radiotherapy (median dose 33 Gy in six fractions over 3 weeks) was given to 95 patients (28%) and conventionally fractionated radiotherapy (median dose 48 Gy in 20 fractions over 4 weeks) to 240 patients (72%). Five-year lymph node field control rates were 86.0% (95% confidence interval 78.4–94.4%) for the hypofractionated group and 85.5% (95% confidence interval 80.5–90.7%) for the conventional fractionation group (P = 0.87). There were no significant differences in recurrence-free survival (RFS) (41.7%, 95% confidence interval 32.5–53.5 versus 31.9%, 95% confidence interval 26.1–38.9; P = 0.18) or overall survival (41.2%, 95% confidence interval 32.1–52.8 versus 45.0%, 95% confidence interval 38.7–52.4; P = 0.77). On multivariate analysis, extranodal spread was associated with decreased RFS (P = 0.04) and the number of resected lymph nodes containing metastatic melanoma was associated with decreased RFS (P = 0.0006) and overall survival (P = 0.01). ConclusionLymph node field control rates, RFS and overall survival were similar after hypofractionated and conventionally fractionated adjuvant radiotherapy. The presence of extranodal spread and an increasing number of positive lymph nodes were predictive of an unfavourable outcome.

Practice Patterns of Treatment Strategy of Limited-Stage Small-Cell Lung Cancer: Survey of Chinese Oncologists.

BackgroundThoracic radiotherapy (TRT) with concurrent chemotherapy is the standard treatment of limited-stage small-cell lung cancer (LS-SCLC). However, there is still a controversy surrounding the treatment strategy especially optimal dosing and fractionation schedule. Current practice patterns among Chinese oncologists are unknown.Materials and MethodsWe surveyed 212 Chinese oncologists using a questionnaire including 50 questions designed by experienced oncologists. Questions covered demographic data, treatment recommendations, and self-assessed knowledge of guidelines or key clinical trials for SCLC. The chi-square test and Fisher’s exact test were utilized to describe the result of the study.ResultsThe response rate was 97% (207/212). Of all the respondents, 69% preferred TRT QD, 29% preferred BID, and 2% chose HFRT. For those who prefer TRT QD, 72% preferred a total dose of 60 Gy, followed by 15% opting for 66 Gy, 12% for <60 Gy, and 1% for 70 Gy. Of those who prefer BID, 79% preferred a total dose of 45 Gy, with 4% choosing 30 Gy, 8% choosing 50 Gy, 7% choosing 54 Gy, and 2% choosing >54 Gy. Regarding PCI, 82% of participants believed that PCI should be performed when treatment is completed and 13% believed that PCI should begin immediately after concurrent chemoradiotherapy. As for other therapies, 26% of participants choose concurrent anti-angiogenic therapy during SCLC treatment, and 49% recommended small-molecule TKI as the main anti-angiogenic therapy.ConclusionSubstantial variation exists in how Chinese oncologists approach TRT dosing and fractionation for LS-SCLC. Almost 70% of respondents reported administering TRT QD more often in daily work. The most common doses were 60 Gy QD and 45 Gy BID.

Assessing the Accuracy of Bioluminescence Image-Guided Stereotactic Body Radiation Therapy of Orthotopic Pancreatic Tumors Using a Small Animal Irradiator.

Stereotactic body radiation therapy (SBRT) has shown promising results in the treatment of pancreatic cancer and other solid tumors. However, wide adoption of SBRT remains limited largely due to uncertainty about the treatment's optimal fractionation schedules to elicit maximal tumor response while limiting the dose to adjacent structures. A small animal irradiator in combination with a clinically relevant oncological animal model could address these questions. Accurate delivery of X rays to animal tumors may be hampered by suboptimal image-guided targeting of the X-ray beam in vivo. Integration of bioluminescence imaging (BLI) into small animal irradiators in addition to standard cone-beam computed tomography (CBCT) imaging improves target identification and high-precision therapy delivery to deep tumors with poor soft tissue contrast, such as pancreatic tumors. Using bioluminescent BxPC3 pancreatic adenocarcinoma human cells grown orthotopically in mice, we examined the performance of a small animal irradiator equipped with both CBCT and BLI in delivering targeted, hypo-fractionated, multi-beam SBRT. Its targeting accuracy was compared with magnetic resonance imaging (MRI)-guided targeting based on co-registration between CBCT and corresponding sequential magnetic resonance scans, which offer greater soft tissue contrast compared with CT alone. Evaluation of our platform's BLI-guided targeting accuracy was performed by quantifying in vivo changes in bioluminescence signal after treatment as well as staining of ex vivo tissues with γH2AX, Ki67, TUNEL, CD31 and CD11b to assess SBRT treatment effects. Using our platform, we found that BLI-guided SBRT enabled more accurate delivery of X rays to the tumor resulting in greater cancer cell DNA damage and proliferation inhibition compared with MRI-guided SBRT. Furthermore, BLI-guided SBRT allowed higher animal throughput and was more cost effective to use in the preclinical setting than MRI-guided SBRT. Taken together, our preclinical platform could be employed in translational research of SBRT of pancreatic cancer.

A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules.

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy.

Safety and Early Efficacy of Involved Field SBRT for Nodal Oligo-Recurrent Prostate Cancer

<h3>Purpose/Objective(s)</h3> Following definitive treatment for localized prostate cancer a subset of men will unfortunately develop recurrent disease. Newer PET agents have demonstrated that most early recurrences occur in the abdominopelvic nodal basins. The optimal treatment strategy for this patient population is unknown but likely includes a combination of systemic therapy, surgery and/or radiation therapy. For radiation therapy, the optimal treatment volume, fractionation schedule and dose remain unanswered questions. We report early outcomes for patients treated with involved field SBRT for nodal oligo-recurrent prostate cancer. <h3>Materials/Methods</h3> Between January 2018 and January 2020, 21 patients with nodal oligo-recurrent prostate cancer treated with involved field SBRT at a single academic institution were eligible for inclusion in this analysis. Detection of recurrence was ascertained by imaging including: Axumin PET/CT (66%) or MRI/CT (34%) following a PSA rise. All patients were treated with five-fraction involved field SBRT to a dose of 27.5-30 Gy. The treatment volume for involved field was defined as the nodal basin containing the gross nodal disease as well as the immediately adjacent nodal basins. Oligo-recurrence was defined as any volume of disease that could be safely treated within an involved field. Acute and late toxicity data was defined as any treatment related toxicity occurring <b>≤</b> 90 days and > 90 days following treatment, respectively. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0. PSA response was defined as any decrease in the PSA following treatment. Local recurrence was defined as any new or growing lesion within the treatment field following treatment. Local control was calculated using the Kaplan-Meier method. <h3>Results</h3> The median pre-salvage PSA was 7.2 ng/ml. The median follow-up for all patients was 25 months (11 – 36 months). The most common acute side effect was grade 1 diarrhea (n = 7, 33%). Acute grade 2 GI toxicity occurred in 14% of patients (n = 3). Two patients had late low grade pelvic pain and 1 patient had late grade 2 lower extremity limb edema. There were no late grade 2+ GI side effects. No grade 3+ side effects occurred at any time following treatment. 88% of patients had a PSA response following treatment. The local control at 1 and 2 years was 100% and 94%, respectively. <h3>Conclusion</h3> With the widespread adoption of novel PET agents the group of patients with oligo-recurrent nodal disease is likely to increase significantly. The optimal combination of local and systemic therapy in this patient population is the subject of ongoing clinical investigation. With a favorable toxicity profile, high rates of local control and PSA response, involved field SBRT represents a feasible as well as convenient local therapy treatment option for an elderly patient population.

Optimizing STING Activity in Prostate Cancer Pre-Clinical Models

We previously showed that radiotherapy (RT) combined with anti-PD-L1 induced abscopal response and prolonged overall survival in a pre-clinical mouse model of prostate cancer. We sought to optimize STimulator of Interferon Gene pathway (STING) activation in vitro and to enhance the abscopal response in our in vivo model.We quantified STING-activator cytosolic dsDNA following RT in 5 prostate cancer cell lines - MycCaP, PC3, 22Rv1, DU145, and LN-CaP. We tested the effects of parameters such as dosing, time after RT exposure, and fractionation. We evaluated PD-L1 expression via Western blotting in parallel experiments. We repeated the published RT and ant-PD-L1 regimen that induced an abscopal response in vitro, but we tested whether anti-PD-L1 administered 1 week before or after RT affected survival.With single doses of RT, the cell lines produced the most cytosolic dsDNA with doses between 12 and 15 Gy. Mathematical modeling of the combined cell lines showed peak production at 13.2 Gy. LN-CaP, the only androgen-sensitive cell line, produced 91-97% less cytosolic dsDNA than the other cell lines. Production of cytosolic dsDNA peaked 8-24 hours after RT and declined to baseline 72 hours after RT. RT doses of 8, 13, or 20 Gy were delivered at various frequencies including: once, once daily x 2 days, once daily x 3 days, every other day x 2 doses, or every other day x 3 doses. Cytosolic dsDNA production was not significantly different between the MycCap and PC3 cell lines. However, max production for MycCap cells occurred with 13 Gy delivered every other day x 3 doses whereas max production for PC3 cells occurred with 13 Gy delivered once daily x 3 days. PD-L1 expression was highest in MycCaP cells exposed correlated with production of cytosolic dsDNA throughout parallel experiments. Within the fractionation scheme, PD-L1 expression was consistently the highest with 13 Gy compared to either 8 Gy or 20 Gy, regardless of fractionation. Finally, median overall survival was unchanged in our mouse model with anti-PD-L1 administered either before or after RT. However, survival at 100 days was significantly different, with 40% vs 0% survival in the cohort treated with anti-PD-L1 before vs after RT.We defined optimal dosing, timing and fractionation schedule for generating cytosolic dsDNA in prostate cancer. Cytosolic dsDNA is correlated with expression of PD-L1, adding evidence that STING induces PD-L1 expression in prostate cancer as similarly reported in other malignancies. Though median overall survival was similar regardless of timing of anti-PD-L1, a percentage of mice exhibited prolonged survival with anti-PD-L1 administered prior to RT. These results guide optimal STING activation in prostate cancer-related pre-clinical studies and will provide the basis for future mechanistic studies regarding STING activation in prostate cancer.

Is hypofractionation acceptable for prostate bed radiotherapy?

Approximately 30% of patients who undergo radical prostatectomy for prostate cancer develop disease progression. The only potentially curative treatment in these patients is postoperative radiotherapy with or without hormonotherapy. One of the standards of care in nonsurgical patients is hypofractionated radiotherapy. However, the current evidence based is insufficient to define the optimal dose and fractionation schedule for postoperative radiotherapy. In this context, the aim of this editorial is to assess the main efficacy and toxicity data for postoperative hypofractionated radiotherapy and discuss the potential to implement this fractionation in routine clinical practice.

Radiotherapy-Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

Simple SummaryRadiotherapy is an important component of cancer treatment, given to around half of all cancer patients. Radiotherapy is known to be very effective at directly killing cancer but, until recently, the important effects that radiotherapy has on the surrounding immune cells were not widely appreciated. Over the last decade, immunotherapy approaches have made a major breakthrough in cancer treatment, and now play an important part of routine cancer care. Given that both radiotherapy and immunotherapy can stimulate anti-tumor immune response, it is logical to combine these approaches to try and improve anti-tumor immunity and cancer outcomes further. This review assesses the important clinical questions that need to be addressed to successfully combine radiotherapy and immunotherapy treatments by rethinking approaches to the delivery of radiotherapy, as well as the optimal type and scheduling of immunotherapy.Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations.

Moderately accelerated intensity-modulated radiation therapy using simultaneous integrated boost: Practical reasons or evidence-based choice? A critical appraisal of literature.

Concurrent chemo-radiotherapy is the non-surgical mainstay of treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). The following aspects have emerged as fundamental components of the combined approach: first, intensity modulated radiotherapy (IMRT) is the minimum standard technical requirement, with level 1 evidence in support of its reduction of late treatment-induced morbidity in comparison with 3D conformal radiotherapy. Second, cisplatin-based chemotherapy is the preferred systemic agent to be associated with radiation, with 100 mg/m2 every 3 weeks deemed as the reference schedule. Because of significant progress in irradiation techniques achieved in last 15 years, the optimal fractionation schedule in modern radiation era remains controversial, especially for locally advanced disease. The purpose of this work was to perform a critical review on the value of moderately accelerated IMRT using simultaneous-integrated boost (SIB) in HNSCC, aiming to provide insights on current clinical practice and directions for future research.

Identifying the Optimal Fractionation Schedules for Improved Response Rates and Survival in Patients with Metastatic Melanoma Treated with Ipilimumab and Radiotherapy

Objective: There is a growing body of evidence that combining ipilimumab with higher doses of radiotherapy may improve the response rates and survival in patients with metastatic melanoma compared to lower doses of radiotherapy. However, the dose cutoff at which improved outcomes are more likely to occur has not been properly identified. Methods: We conducted a retrospective analysis of 100 patients treated with ipilimumab and radiotherapy for metastatic melanoma at a single institution from May 2011 to January 2017. Demographic, clinical, and treatment factors, including the biological equivalent dose (BED) with an α/β of 7, were recorded. Endpoints of interest included infield and global complete response (CR) after the completion of radiation and ipilimumab based on the RECIST criteria (v1.1) and 12-month overall survival (OS). Results: The BED cutoffs at which improved outcomes are more likely to occur are 46.5 Gy for infield CR, 50.9 Gy for global CR, and 46.5 Gy for 12 month OS. The least aggressive fractionation schedules used in this patient population that have a BED above the threshold for all 3 outcomes include 40 Gy in 20 fractions, 30 Gy in 6 fractions, and 24 Gy in 3 fractions. Conclusion: This hypothesis-generating study suggests that patients who cannot receive ablative intent radiotherapy may be more likely to benefit from concurrent radiotherapy with ipilimumab if their fractionation schedule has a BED above 46.5 - 50.9 Gy. Prospective trials evaluating this question should be considered.