BACKGROUND:Surgical stabilization followed by postoperative radiotherapy (RT) is the standard of care for impending pathologic fractures due to bone metastases. Compared with conventional RT, stereotactic body RT (SBRT) provides more durable tumor control and palliation, but treatment volume constraints often preclude postoperative use. Preoperative SBRT limited to the tumor volume offers a solution by delivering an ablative dose before intraoperative tumor dissemination, but its safety is not established. METHODS:We conducted a phase I, nonrandomized clinical trial at a quaternary care cancer center, with accrual between June 2021 and April 2024. Eligible patients (N=38) had pelvic or long bone metastases with impending pathologic fractures requiring surgical stabilization. Patients received preoperative SBRT (27-30 Gy in 3 fractions or 18-24 Gy in 1 fraction) followed by surgical stabilization within 1 week. The primary endpoint was rate of wound complications within 6 weeks after preoperative SBRT and surgical stabilization. Secondary endpoints were rates of tumor recurrence and grade ≥3 treatment-related toxicities within 1 year. RESULTS:A total of 7 patients were excluded due to inability to receive treatment or death prior to the primary endpoint. Thirty-one patients were evaluated at 6 weeks postoperatively, 26 at 3 months, and 16 at 1 year. The median age was 66 years (IQR, 59-71), and 15 (48%) patients were male. At 6 weeks, 2 of 31 patients (6.5%; 95% CI, 0.79-21.4) experienced wound complications. At 3 months, 1 of 26 patients (3.8%; 95% CI, 0.10-19.6) experienced grade ≥3 treatment-related toxicity. At 12 months, 1 of 16 patients (6.3%; 95% CI, 0.16-30.2) had tumor recurrence. CONCLUSIONS:Preoperative SBRT is associated with a low risk of wound complications and durable local tumor control. A randomized controlled trial examining its efficacy, potential to facilitate less invasive surgery, and impact on functional outcomes is warranted. CLINICALTRIALS:gov identifier: NCT05038124.

Sentinel lymph node biopsy (SLNB) is increasingly omitted in early-stage breast cancer, often prompting whole-breast irradiation (WBI). We evaluated partial-breast irradiation (PBI) without axillary surgery among 78 clinically node-negative patients (median age 75) treated from 2014-2022. After 53-month median follow-up, no ipsilateral, regional, or distant recurrences occurred. These results demonstrate excellent outcomes and suggest PBI is a feasible, safe alternative to WBI when SLNB is omitted.

Purpose We aimed to evaluate the acceptability, appropriateness, and feasibility of using an electronic patient-reported outcome (ePRO)-based strategy to reduce postradiation therapy (RT) visits in patients with breast cancer who reported minimal symptoms. Methods and Materials An ePRO instrument was administrated weekly for patients undergoing RT for breast cancer at an academic cancer center. The instrument assessed RT toxicities (breast enlargement/tenderness, skin changes, pain, and fatigue) using Patient-Reported Outcomes National Cancer Institute Common Terminology Criteria for Adverse Events and anxiety with the Generalized Anxiety Disorder 2-item screening tool. Patients rated symptom severity on a 5-point Likert scale (none to very severe). Six weeks after treatment completion, patients with no more than moderate symptoms were offered the option to cancel their routine post-RT follow-up visit. Clinical and demographic data were collected from electronic health records. Results Among the 46 patients (median age: 60 years) who responded to the appointment cancellation question, 32 (70%) were White, 5 (11%) Black, 5 (11%) Asian, and 2 (4.3%) Hispanic. Regarding acceptability among respondents, we found 36 (78%) chose to keep their appointments, 7 (15%) opted to cancel, and 3 (6.5%) were not sure. In terms of appropriateness, patients who canceled or were unsure were similar in age, race, ethnicity, body mass index, and travel distance to the center, but reported fewer symptoms than those who kept their appointments, with significantly lower breast tenderness (10% vs 50%, respectively, P = .026), and a trend toward lower pain in the radiated area (30% vs 61%, P = .073) and fatigue (30% vs 56%, P = .23). As an assessment of feasibility, fewer hospitalizations within 6 months occurred among those cancelling their follow-up visit (0 vs 2 [5.6%]), whereas urgent care visits were comparable (8.6% vs 10%). Conclusions An ePRO-based strategy to inform post-RT follow-up visits appears feasible and appropriate for patients who completed breast RT with mild-to-moderate symptoms. Despite low acceptability (∼20%), the high prevalence of breast cancer suggests this strategy could still reduce the clinical burden of low-value visits.

PURPOSE:The 5-year results of the FAST-Forward trial demonstrated noninferiority of local tumor control using a 26 Gy in 5 fraction regimen compared with 40 Gy in 15 fractions for breast cancer patients receiving adjuvant whole breast radiation therapy (WBRT) with or without a sequential conventionally fractionated tumor bed boost (2 Gy per fraction). Here, we reported our institutional experience using the FAST-Forward regimen with a novel sequential boost regimen of 5.2 Gy in 1 fraction or 10.4 Gy in 2 fractions. METHODS AND MATERIALS:Patients with nonmetastatic invasive breast cancer or ductal carcinoma in situ treated with adjuvant WBRT of 26 Gy in 5 fractions from January 7, 2019, to January 6, 2022, were identified from an institutional database. Clinical outcomes, including adverse events, disease control, and patient-reported outcomes, were collected. Survival outcomes were estimated using the Kaplan-Meier method. Associations between toxicities and clinicopathologic and treatment characteristics were assessed using logistic regression. RESULTS:A total of 311 consecutive patients were included; the use of a 1- or 2-fraction boost was left to the discretion of the treating physicians (54% 1-fraction, 8.7% 2-fraction, and 38% no boost). Median follow-up was 32 months. Overall survival and local recurrence-free survival probabilities at 36 months were 96% (95% CI, 94-99) and 93% (95% CI, 90-97), respectively. Acute and late toxicities occurred at a higher rate in the 2-fraction versus 1-fraction and no boost groups (37.4%, 10.8%, and 12.2% [acute] and 22.7%, 8.6%, and 7.9% [late], respectively). Boost receipt, greater boost volume, 15× energy, increasing breast V95%, and bolus use were associated with the risk of acute grade ≥ 2 toxicities. CONCLUSION:A 5-fraction ultrahypofractionated WBRT regimen for early-stage breast cancer with either no boost or a single-fraction boost of 5.2 Gy resulted in excellent disease control and acceptable toxicity. Increased toxicity was observed with a boost of 10.4 Gy in 2 fractions and is no longer used at our institution.

Importance:De-escalation of adjuvant therapy is feasible for select older patients with early-stage breast cancer. It is not known whether we can expand de-escalation options for younger patients by incorporating genomic biomarkers, such as the Oncotype DX 21-gene recurrence score (ODX RS). Objective:To evaluate outcomes of radiotherapy (RT) or endocrine therapy (ET) de-escalation for patients aged 50 to 69 years with early-stage breast cancer and an ODX RS of 18 or below. Design, Setting, and Participants:This cohort study was conducted at a comprehensive cancer center among patients aged 50 to 69 years with T1N0, hormone receptor-positive, ERBB2-negative breast cancer, with an ODX RS of 18 or below. Patients were treated between January 2007 and January 2023 with lumpectomy and ET, with or without adjuvant RT. Patients were considered adherent to ET if they received 5 years of ET or more, or if it was ongoing at last follow-up; nonadherence included halting ET within 5 years after initiation. Main Outcomes and Measures:Cumulative incidence of locoregional recurrence (LRR) was the primary end point, with death and non-local-regional events as competing risks. Results:This analysis included 2249 patients (median [IQR] age, 60 years [55-65 years]) with a median (IQR) follow-up of 63.3 months (34.1-96.0 months), of whom 2075 (92.3%) received RT. The 72-month cumulative incidence of LRR without RT was 8.0% (95% CI, 3.0%-16.0%) vs 1.1% with RT (95% CI, 0.6%-1.7%) (P < .001). When stratified by RT and ET adherence, patients receiving RT had the lowest LRR risk regardless of ET duration (72-month LRR: RT and ET adherence, 1.1% [95% CI, 0.6%-2.1%] vs RT and ET nonadherence, 0.9% [95% CI, 0.3%-2.1%]). Adherence to ET alone (without RT) had an estimated 72-month LRR of 5.5% (95% CI, 1.0%-16.0%). Those who did not receive RT and were ET nonadherent had an estimated 72-month LRR of 11.0% (95% CI, 3.3%-25.0%). No association was observed between receipt of RT and OS (P = .2). Conclusions and Relevance:In this cohort study of patients aged 50 to 69 years who underwent lumpectomy for early-stage breast cancer with ODX RS of 18 or below, we found significantly lower estimated LRR rates among those who completed at least 1 form of adjuvant therapy. For patients willing to accept a low absolute risk, but slightly higher relative risk of LRR with de-escalated therapy, ODX RS may be a valuable tool in selecting younger candidates for RT omission than current guidelines support.

Purpose We hypothesized that favorable genomic scores could identify patients with NCCN high-risk prostate cancer that are suitable for de-intensification of androgen deprivation therapy (ADT) and a compressed course of radiation therapy. Methods This single arm, phase II prospective study enrolled 50 patients with a Decipher genomic classifier (GC) score ≤0.6 and localized, high-risk prostate cancer defined as Gleason grade group 4 or 5, PSA > 20 ng/mL, or cT3-4N0M0. Patients were treated with 6 months of neoadjuvant/concurrent/adjuvant ADT (leuprolide + bicalutamide) combined with a single 15 Gy Ir-192 HDR brachytherapy implant followed by 25 Gy in 5 daily fractions whole pelvis SBRT. The primary endpoint was 3-year metastasis rate. Only early toxicity (CTCAE v5.0), International Prostate Symptom Score (IPSS), and biochemical recurrence rate (defined as PSA nadir + 2 ng/mL) are reported. Results The median age of enrolled patients was 68.5 years old, with a median Decipher GC score of 0.405 [95%CI 0.361 - 0.433], and median baseline PSA of 6.83 [95%CI 5.98 - 8.77]. Pre-treatment MR imaging showed PIRADS 4 or 5 lesions in 84% (42/50) of enrolled patients and pre-treatment biopsies showed Gleason grade group 4 or 5 disease in 64% (32/50) of patients. The median follow-up across all enrolled patients was 22 months [95%CI 19.69 - 23.55], and thus only early secondary endpoint outcomes are reported. Median baseline IPSS was 4 [95%CI 3.93 - 6.15], while median IPSS at first follow up was 9.54 [95%CI 7.73 - 11.35] and at most recent follow up was 6.62 [95%CI 5.09 - 8.14]. Grade 2 GU toxicity was seen in 32% (16/50) patients, while grade 2 GI toxicity was seen in 14% of patients (7/50). No grade 3 or higher toxicities were seen. Median time to testosterone recovery was 10 months [95%CI 9.34 - 11.03]. The rate of biochemical recurrence was 2% (1/50). Conclusions Thus far, we have observed low GU/GI toxicity, preserved GU quality of life, and encouraging early oncological outcomes with a shorter course of ADT and RT for genomically lower risk, NCCN high-risk prostate cancer patients. Longer follow-up is needed to report the primary endpoint of 3-year metastasis-free survival.

352 Background: The incidence of regional lymph node metastases at diagnosis is approximately 15%. Androgen deprivation therapy (ADT) with radiotherapy (RT) remains a standard treatment option, but long-term effects and outcomes are understudied. Methods: Data was retrospectively collected from 304 subjects with radiographic node-positive prostate cancer treated with RT from 2014-2024. Covariates include use of androgen receptor signaling inhibitors (ARSI), use of brachytherapy boost to primary disease in prostate, pre-RT PSA, and Gleason Score (GS). Endpoints included biochemical progression (bPFS), distant metastases free survival (DMFS) and overall survival (OS). Kaplan-Meier method, log rank test, univariate (UVA) and multivariate regression analyses (MVA) were used for time to event endpoints. Results: Patient features are summarized in table. 48% of patients had ECOG 0. On MVA, GS 9-10 was significantly associated with worse OS (HR 2.26, 95%CI 1.15 – 4.43, p=0.02), DMFS (HR 2.37, 95%CI 1.32 – 4.24, p<0.01) and bPFS (HR 2.10, 95%CI 1.23 – 3.59, p<0.01). Worse performance status was associated with significantly worse OS (HR 3.14, 95%CI 1.35 – 7.29, p<0.01), DMFS (HR 2.03, 95%CI 0.95 – 4.35, p=0.07) and bPFS (HR 2.01, 95%CI 0.99 – 4.07, p=0.05). Radiation boost dose to involved lymph nodes was significantly associated with OS (p=0.03) and DMFS (p=0.03) but not bPFS. There were no other statistically significant associations on MVA. There was no significant association on UVA between pre-radiation maximum PSA and OS, DMFS, or bPFS. Conclusions: In this cohort of patients treated with ADT and definitive RT, 5-year DMFS was 67%. Gleason score and age were the strongest prognostic features. There was no significant association, but there was numerically higher survival seen with use of ARSI or brachytherapy boost. Future work includes characterizing patterns of care and failure to help optimize management. Characteristics and univariable regression results for OS, DMFS, and bPFS using age and pre-RT PSA as continuous variables. N (%) 5yr OS HR (95%CI) p-value 5yr DMFS HR (95%CI) p-value 5yr bPFS HR (95%CI) p-value Age (continuous) Median age (IQR) 69 (64 – 75) 74% 1.04 (1.00 – 1.09) p=0.07 67% 1.02 (0.99 – 1.06) p=0.2 65% 1.02 (0.99 – 1.05) p=0.3 Gleason 8 156 (54%) 83% 74% 71% 9-10 135 (46%) 69% 2.05 (1.06 – 3.95) p=0.03 62% 2.17 (1.25 – 3.77) p<0.01 60% 2.06 (1.22 – 3.49) p<0.01 Brachytherapy Use Yes 86 (28%) 80% 0.60 (0.27 – 1.35) p=0.2 79% 0.62 (0.31 – 1.22) p=0.2 79% 0.61 (0.32 – 1.16) p=0.13 ARSI Use Yes 182 (60%) 78% 0.91 (0.50 – 1.64) p=0.7 67% 0.90 (0.54 – 1.50) p=0.7 67% 0.79 (0.48 – 1.29) p=0.3 Volume Nodal Boost – Below median Median (IQR) 16.1 cc (7.3 – 33.9) 76% 0.99 (0.54 – 1.80) p>0.9 72% 0.93 (0.55 – 1.56) p=0.8 68% 1.05 (0.64 – 1.73) p=0.8 Volume of radiographically involved lymph nodes assessed as binary variable.

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer, defined as mammary carcinoma with squamous or mesenchymal differentiation, that may include spindle cell, chondroid, osseous, or rhabdomyoid differentiation patterns. The implications of MBC recurrence and survival outcomes remains unclear. Cases were ascertained from a prospectively maintained institutional database of patients treated from 1998 to 2015. Patients with MBC were matched 1:1 to non-MBC cases. Cox proportional-hazards models and Kaplan–Meier estimates were used to evaluate outcome differences between cohorts. 111 patients with MBC were matched 1:1 with non-MBC patients from an initial set of 2400 patients. Median follow-up time was 8 years. Most patients with MBC received chemotherapy (88

Purpose: We aimed to develop and study the implementation of a remote system for toxicity assessment and management of acute side effects of breast radiation using electronic patient-reported outcomes (ePROs). Methods and Materials: A response-adapted Patient-Reported Outcomes Common Terminology Criteria for Adverse Events -based assessment for breast radiation toxicity was administered weekly during and for 8 weeks after radiation from June 2019 to July 2020. The care team received alerts when "severe" symptoms were reported by patients, who were then contacted. Treatment, clinic, and sociodemographic characteristics were abstracted from patient records. A subsample of patients and care team members was qualitatively interviewed at follow-up. Results: Overall, 5787 assessments were sent to 678 patients, of whom 489 (72%) completed 2607 assessments (45%). Moderate or greater toxicity was reported by 419 responders (86%; 95% CI, 82%-89%). Clinician alerts for severe toxicity were generated for 264 assessments among 139 unique patients, of which 83% occurred posttreatment. The proportion of surveys that prompted an alert was significantly higher after treatment (219 [13%]) than during treatment (45 [5%]) (P < .001). Survey completion rates in the posttreatment period were higher among patients undergoing partial breast irradiation than postmastectomy radiation (incidence rate ratio, 0.70; 95% CI, 0.60-0.81) (P < .001) despite these patients experiencing less severe toxicity. Interviews (15) found that patients had a positive experience with ePROs, although many thought the primary purpose was for research rather than symptom management. Conclusions: With the majority of toxicity occurring after breast radiation has ended, remote symptom monitoring with ePROs appears to fill a gap in clinical practice, particularly for patients undergoing shorter courses of radiation. It is important to properly onboard patients and explain that the purpose of ePROs is to aid clinical care. Further research is needed to determine whether the costs associated with ePROs can be offset by reducing routine clinic visits and whether this approach is acceptable and appropriate. (C) 2021 Elsevier Inc. All rights reserved.

OBJECTIVE:Patients with metastatic thyroid cancer have prolonged survival compared to those with other primary tumors. The spine is the most common site of osseous involvement in cases of metastatic thyroid cancer. As a result, obtaining durable local control (LC) in the spine is crucial. This study aimed to evaluate the efficacy of spine stereotactic radiosurgery (SSRS) in patients with metastatic thyroid cancer. METHODS:Information on patients with metastatic thyroid cancer treated with SSRS for spinal metastases was retrospectively evaluated. SSRS was delivered with a simultaneous integrated boost technique using single- or multiple-fraction treatments. LC, defined as stable or reduced disease volume, was evaluated by examining posttreatment MRI, CT, and PET studies. RESULTS:A total of 133 lesions were treated in 67 patients. The median follow-up duration was 31 months. Dose regimens for SSRS included 18 Gy in 1 fraction, 27 Gy in 3 fractions, and 30 Gy in 5 fractions. The histology distribution was 36% follicular, 33% papillary, 15% medullary, 13% Hurthle cell, and 3% anaplastic. The 1-, 2-, and 5-year LC rates were 96%, 89%, and 82%, respectively. The median overall survival (OS) was 43 months, with 1-, 2-, and 5-year survival rates of 86%, 74%, and 44%, respectively. There was no correlation between the absolute biological equivalent dose (BED) and OS or LC. Patients with effective LC had a trend toward improved OS when compared to patients who had local failure: 68 versus 28 months (p = 0.07). In terms of toxicity, 5 vertebral compression fractures (2.8%) occurred, and only 1 case (0.6%) of greater than or equal to grade 3 toxicity (esophageal stenosis) was reported. CONCLUSIONS:SSRS is a safe and effective treatment option with excellent LC and minimal toxicity for patients with metastatic thyroid cancer. No association with increased radiation dose or BED was found, suggesting that such patients can be effectively treated with reduced dose regimens.

Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques-immunotherapy and SABR-in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments.

Background: Metastatic deposits to the spine in thyroid cancer patients represent the most common site of bone involvement and can contribute to pain, neurologic deficits, and death. This study sought to determine the efficacy and safety of spine stereotactic radiosurgery (SSRS) for thyroid cancer patients.Methods: Thyroid cancer patients with spine metastases were selected and analyzed from a cohort of patients who were prospectively enrolled in two single-institution Phase I/II studies. SSRS was delivered in single or multi-fraction schedules. Dose regimens ranged from 16-18 Gy in one fraction to 27-30 Gy in three to five fractions. Toxicity was graded according to the NCI-CTC toxicity scale. Local control was determined by serial post-treatment magnetic resonance imaging scans showing no evidence of progressive disease. Patients were followed until date of death or date of last known visit for survival analyses. Local control and overall survival rates were carried out using Kaplan-Meier estimates. The log-rank test was used to assess the equality of the survivor function across groups. A p-value of <= 0.05 was considered to be statistically significant.Results: A total of 27 spine lesions were treated in 23 patients over a six-year period. Median follow-up was 28.9 months (range 5-93 months). Local control was 88% at two years and 79% at three years. In patients with progressive disease following conventional radiation therapy, local control for salvage SSRS remained at 88% at three years. Patients requiring upfront surgical intervention and treated with adjuvant SSRS achieved sustained control rates of 86% at three years. Overall survival rates were 85% and 67% at one and two years, respectively. In patients classified with oligoprogression and controlled extra-spinal disease, overall survival was significantly higher than those with evidence of systemic progression (81% vs. 45% at two years; p = 0.01). Univariate analysis did not show significant correlations between local control and age, systemic disease status, prior 131 I therapy, SSRS fraction regimen, spine location, histological subtype, or time from initial diagnosis to evidence of spinal metastasis. No patient experienced any grade 3-5 toxicity. Pain flare was reported in 30% of patients, with only three patients (13%) requiring narcotics or short-course steroids. There was no evidence of vertebral body fracture in any patient that achieved local control in the treated area.Conclusions: SSRS for thyroid metastases as a primary or adjuvant/salvage therapy is well tolerated and yields high rates of local control.

Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen-specific T cells with proton radiation therapy to exploit the activity of those T cells.Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences.Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells.Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options. Published by Elsevier Inc.

Current literature supports that, in addition to direct cell death, photon irradiation can stimulate tumor-specific immune responses. As the use of proton radiation therapy continues to evolve and expand beyond the pediatric population, its clinical applications now encompass patients with primary tumors of the prostate, head and neck, lung, breast, and central nervous system. In this study, we investigate the ability of proton irradiation to induce antitumor immunity. Cells of human lung [H460, H1703], breast [MDA-MB-231], and prostate [LNCaP] carcinoma were chosen for investigation. Cells were irradiated in a single fraction of 8 CGE (Cobalt Gray Equivalent) or left untreated. Cells were harvested 96 hours after proton irradiation for flow cytometry analysis and cytotoxic assays. Surface staining of tumor cells was performed using the primary labeled monoclonal antibodies and appropriate isotype-matched controls. Adherent cells were used as targets in tumor-antigen specific T-cell cytotoxicity assays using 111In. Supernatant was decanted from treated and untreated flasks and utilized for cytokine production analyses. Significant differences in the distribution of flow cytometry analysis data were determined by the Kolmogorov–Smirnov test. Additional statistical analyses were derived using one-way ANOVA with Tukey's multi-comparison test. p-values less than 0.05 were considered statistically significant. Following proton irradiation, all cell lines showed increased surface expression of the immunostimulatory markers, HLA-ABC, ICAM-1, CD70, 4-1BBL, OX40-L, and ICOS-L in terms of percent positive cells or mean fluorescence intensity (MFI). Conversely, the immunosuppressive marker, PD-L1, significantly decreased its surface expression in LNCaP cells from 44% to 33% following treatment. MDA-MB-231, H460, and preliminary results with a chordoma cell line [UCH-1] all maintained high levels of IL-6 production, a pro-inflammatory cytokine, following proton radiation therapy. Compared to untreated cells, the level of cytotoxicity increased nearly 3-4-fold in LNCaP (p<0.01), H1703 (p<0.01), and MDA-MB-231 (p<0.01) after exposure to protons. Our results show that proton radiation therapy is effective at modulating cancer cell phenotypes and increases surface expression of immunostimulatory markers with concomitant decreases in immunosuppressive markers. Further, immune recognition of tumor cells was heightened, resulting in inflammatory cytokine production and enhanced cytotoxicity. These preliminary studies may shed light as to the possibility of combining proton therapy with immunotherapeutic strategies.

As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients.

We sought to determine if single-dose external beam radiation therapy (EBRT) could modulate the expression signature of T-cell costimulatory and coinhibitory molecules in human prostate cancer (PCa) cell lines in vitro. We investigated the functional impact of irradiated PCa cells with a modulated costimulatory profile on responder T-cell activity. We used three PCa cell lines (DU145, PC3, and LNCaP) and two epithelial cell lines from noncancerous prostate and lung tissue. After 72 hours of EBRT, surface expression of four immunostimulatory molecules (CD70, CD275/ICOSL, CD134L/OX40L, and CD137L/41BBL) and two immunosuppressive markers (CTLA-4/CD152 and PD-L1/CD274) were evaluated by flow cytometry. We evaluated the impact of several radiation doses and the longevity of modulated expression. We examined the functional impact of radiation-induced modulation of cancer cells by cytotoxic T cells (CTL) cytotoxicity and ELISPOT assay for interferon-gamma (IFN-γ) production. Last, we evaluated whether IFN-γ-induced PD-L1 expression could be reversed by EBRT. After 10 Gy EBRT, expression of OX40L and 41BBL increased in all three PCa cell lines; expression of CD70 and ICOSL increased in PC3 cells. Conversely, a decrease in PD-L1 expression in DU145 and PC3 cells was detectable up to 144 hours after EBRT. No PD-L1 was detected in LNCaP. Epithelial cells from normal prostate were not modulated by radiation. CTL cytolytic activity and IFN-γ production were enhanced by interaction with irradiated PCa cells. Finally, EBRT failed to prevent IFN-γ-induced upregulation of PD-L1. We demonstrate that a single dose of EBRT increased surface expression of costimulatory molecules and decreased the expression of coinhibitory molecules in human PCa cell lines. Changes in irradiated tumor cells led to functional enhancement of T-cell activity, despite EBRT failing to reduce IFN-γ-induced expression of PD-L1. These data suggest that combining radiotherapy with T-cell stimulating immunotherapy may be an attractive strategy for cancer treatment.

PURPOSE:To evaluate, in a gynecologic cancer setting, changes in bowel position, dose-volume parameters, and biological indices that arise between full-bladder (FB) and empty-bladder (EB) treatment situations; and to evaluate, using cone beam computed tomography (CT), the validity of FB treatment presumption. METHODS AND MATERIALS:Seventeen gynecologic cancer patients were retrospectively analyzed. Empty-bladder and FB CTs were obtained. Full-bladder CTs were used for planning and dose optimization. Patients were given FB instructions for treatment. For the study purpose, bowel was contoured on the EB CTs for all patients. Bowel position and volume changes between FB and EB states were determined. Full-bladder plans were applied on EB CTs for determining bowel dose-volume changes in EB state. Biological indices (generalized equivalent uniform dose and normal tissue complication probability) were calculated and compared between FB and EB. Weekly cone beam CT data were available in 6 patients to assess bladder volume at treatment. RESULTS:Average (±SD) planned bladder volume was 299.7 ± 68.5 cm(3). Median bowel shift in the craniocaudal direction between FB and EB was 12.5 mm (range, 3-30 mm), and corresponding increase in exposed bowel volume was 151.3 cm(3) (range, 74.3-251.4 cm(3)). Absolute bowel volumes receiving 45 Gy were higher for EB compared with FB (mean 328.0 ± 174.8 vs 176.0 ± 87.5 cm(3); P=.0038). Bowel normal tissue complication probability increased 1.5× to 23.5× when FB planned treatments were applied in the EB state. For the study, the mean percentage value of relative bladder volume at treatment was 32%. CONCLUSIONS:Full-bladder planning does not necessarily translate into FB treatments, with a patient tendency toward EB. Given the uncertainty in daily control over bladder volume for treatment, we strongly recommend a "planning-at-risk volume bowel" (PRV_Bowel) concept to account for bowel motion between FB and EB that can be tailored for the individual patient.

Purpose Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. Material and methods We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). Results The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001). Conclusions Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect.

Purpose/Objective(s)RTOG protocols for Gynecologic disease site require bowel to be contoured on a full-bladder CT, assuming full-bladder treatments with the goal of reducing irradiated bowel volume. We evaluated changes in bowel dose-volume parameters and biological indices that could arise when full-bladder planned treatments are applied in empty-bladder condition. CBCT images will be used to establish validity of full-bladder treatment assumption.Materials/MethodsSeventeen patients treated in our institution for Cervix or Endometrial cancers were retrospectively analyzed. Median age was 62 years (range, 48-88 years) and FIGO stages ranged from IA to IVA. All patients underwent CT/Simulation; Empty (EB) and Full-bladder (FB) CTs were obtained and contouring was performed according to RTOG guidelines. FB CTs were used as primary set for planning and dose optimization. The EBRT prescription dose ranged from 45 to 54 Gy and treatments were delivered using IMRT/VMAT techniques. Patients were given full-bladder instructions for treatment. For the study purpose, bowel was contoured on the EB CTs for all patients. Bowel position and volume changes between FB and EB states were determined in each case. FB treatment plans were applied on EB CTs for determining bowel dose-volume changes due to empty bladder. From the resulting dose distributions, EB bowel dose-volume histogram (DVH) data were obtained and compared with respective FB treatment plan bowel DVHs. From these sets of DVHs, biological indices (gEUD and NTCP) were calculated and compared between FB and EB. Weekly CBCT was available in 6 patients to assess bladder-fill status. From CBCT data, Bladder-fill factors (ratio of (CBCT/Planned) Bladder Volumes) were determined.ResultsAverage bladder volume for FB CTs was 299.7 cc (±68.5 cc). Bowel displacement (vertical drop) between FB and EB was median 17.5 mm (range, 5-39 mm) and corresponding increase in bowel volume was 151.3 cc (range, 74.3-251.4 cc). Absolute bowel volumes receiving 45 Gy were higher for EB compared to FB (mean 328.0 (±174.8) vs 176.0 (±87.5) cc, two-tailed p = 0.0038). The relative increase in bowel gEUD between FB and EB was median 5.4% (range, 0.3%-38%). Bowel NTCP increased 1.5× to 23.5× going from FB to EB, highest for SIB treatment wherein EB would increase bowel volume in high-dose region. The avg. bladder-fill factor during treatments was 0.32 for the study population.ConclusionsOur study has demonstrated that FB planning does not necessarily translate into FB treatments during the course of pelvic Gyn. EBRT. Given the uncertainty in daily control over bladder-fill status for treatment, we strongly recommend bowel contouring and dose limiting be based on “planning at risk volume bowel” (PRV) concept by adding a margin that is tailored for the patient based on bowel displacement between FB and EB states. Purpose/Objective(s)RTOG protocols for Gynecologic disease site require bowel to be contoured on a full-bladder CT, assuming full-bladder treatments with the goal of reducing irradiated bowel volume. We evaluated changes in bowel dose-volume parameters and biological indices that could arise when full-bladder planned treatments are applied in empty-bladder condition. CBCT images will be used to establish validity of full-bladder treatment assumption. RTOG protocols for Gynecologic disease site require bowel to be contoured on a full-bladder CT, assuming full-bladder treatments with the goal of reducing irradiated bowel volume. We evaluated changes in bowel dose-volume parameters and biological indices that could arise when full-bladder planned treatments are applied in empty-bladder condition. CBCT images will be used to establish validity of full-bladder treatment assumption. Materials/MethodsSeventeen patients treated in our institution for Cervix or Endometrial cancers were retrospectively analyzed. Median age was 62 years (range, 48-88 years) and FIGO stages ranged from IA to IVA. All patients underwent CT/Simulation; Empty (EB) and Full-bladder (FB) CTs were obtained and contouring was performed according to RTOG guidelines. FB CTs were used as primary set for planning and dose optimization. The EBRT prescription dose ranged from 45 to 54 Gy and treatments were delivered using IMRT/VMAT techniques. Patients were given full-bladder instructions for treatment. For the study purpose, bowel was contoured on the EB CTs for all patients. Bowel position and volume changes between FB and EB states were determined in each case. FB treatment plans were applied on EB CTs for determining bowel dose-volume changes due to empty bladder. From the resulting dose distributions, EB bowel dose-volume histogram (DVH) data were obtained and compared with respective FB treatment plan bowel DVHs. From these sets of DVHs, biological indices (gEUD and NTCP) were calculated and compared between FB and EB. Weekly CBCT was available in 6 patients to assess bladder-fill status. From CBCT data, Bladder-fill factors (ratio of (CBCT/Planned) Bladder Volumes) were determined. Seventeen patients treated in our institution for Cervix or Endometrial cancers were retrospectively analyzed. Median age was 62 years (range, 48-88 years) and FIGO stages ranged from IA to IVA. All patients underwent CT/Simulation; Empty (EB) and Full-bladder (FB) CTs were obtained and contouring was performed according to RTOG guidelines. FB CTs were used as primary set for planning and dose optimization. The EBRT prescription dose ranged from 45 to 54 Gy and treatments were delivered using IMRT/VMAT techniques. Patients were given full-bladder instructions for treatment. For the study purpose, bowel was contoured on the EB CTs for all patients. Bowel position and volume changes between FB and EB states were determined in each case. FB treatment plans were applied on EB CTs for determining bowel dose-volume changes due to empty bladder. From the resulting dose distributions, EB bowel dose-volume histogram (DVH) data were obtained and compared with respective FB treatment plan bowel DVHs. From these sets of DVHs, biological indices (gEUD and NTCP) were calculated and compared between FB and EB. Weekly CBCT was available in 6 patients to assess bladder-fill status. From CBCT data, Bladder-fill factors (ratio of (CBCT/Planned) Bladder Volumes) were determined. ResultsAverage bladder volume for FB CTs was 299.7 cc (±68.5 cc). Bowel displacement (vertical drop) between FB and EB was median 17.5 mm (range, 5-39 mm) and corresponding increase in bowel volume was 151.3 cc (range, 74.3-251.4 cc). Absolute bowel volumes receiving 45 Gy were higher for EB compared to FB (mean 328.0 (±174.8) vs 176.0 (±87.5) cc, two-tailed p = 0.0038). The relative increase in bowel gEUD between FB and EB was median 5.4% (range, 0.3%-38%). Bowel NTCP increased 1.5× to 23.5× going from FB to EB, highest for SIB treatment wherein EB would increase bowel volume in high-dose region. The avg. bladder-fill factor during treatments was 0.32 for the study population. Average bladder volume for FB CTs was 299.7 cc (±68.5 cc). Bowel displacement (vertical drop) between FB and EB was median 17.5 mm (range, 5-39 mm) and corresponding increase in bowel volume was 151.3 cc (range, 74.3-251.4 cc). Absolute bowel volumes receiving 45 Gy were higher for EB compared to FB (mean 328.0 (±174.8) vs 176.0 (±87.5) cc, two-tailed p = 0.0038). The relative increase in bowel gEUD between FB and EB was median 5.4% (range, 0.3%-38%). Bowel NTCP increased 1.5× to 23.5× going from FB to EB, highest for SIB treatment wherein EB would increase bowel volume in high-dose region. The avg. bladder-fill factor during treatments was 0.32 for the study population. ConclusionsOur study has demonstrated that FB planning does not necessarily translate into FB treatments during the course of pelvic Gyn. EBRT. Given the uncertainty in daily control over bladder-fill status for treatment, we strongly recommend bowel contouring and dose limiting be based on “planning at risk volume bowel” (PRV) concept by adding a margin that is tailored for the patient based on bowel displacement between FB and EB states. Our study has demonstrated that FB planning does not necessarily translate into FB treatments during the course of pelvic Gyn. EBRT. Given the uncertainty in daily control over bladder-fill status for treatment, we strongly recommend bowel contouring and dose limiting be based on “planning at risk volume bowel” (PRV) concept by adding a margin that is tailored for the patient based on bowel displacement between FB and EB states.

Cervical cancer patients with disease extending laterally into parametrial tissue often require interstitial trans-perineal implantation under general anesthesia and a hospital stay for brachytherapy treatments. A major disadvantage of intraoperative implantation is the lack of 3D image guidance during needle placement. Here, we describe real-time CT-guidance to allow interstitial implantation of catheters with the Utrecht Fletcher Applicator® (Nucletron™) in an ambulatory setting. Following a mild oral analgesic and an anxiolytic, patients are placed on the CT simulator couch in the treatment position. The Utrecht tandem and ovoid (T&O) is inserted and a CT scan of the pelvis performed to confirm appropriate geometry. Delineating the extent of disease and organs at risk on the CT scan allows determination of the optimal number, distribution, and depth of insertion of each interstitial catheter. A CT is repeated after insertion of each catheter and adjustments are made in real time. Once all interstitial catheters are implanted, a final CT is performed for 3D optimization brachytherapy planning. Without movement or manipulation, the patients are then treated with HDR brachytherapy on the CT simulator couch. Following therapy, the Utrecht T&O applicator and interstitial needles are removed and patients are discharged home. A total of 77 treatments were performed in 18 patients. Ten out of eighteen patients (56%) required 2 or fewer needles placed to adequately dose the extent of disease. Persistent vaginal bleeding after removal of the applicator was observed in 4 patients necessitating an inpatient stay for close observation with 2 patients requiring blood transfusions. Only one did not continue with the interstitial implantations and was treated with standard T&O implant followed by an external beam parametrial boost. All other patients tolerated the treatments well with no complications documented. Real-time CT-guided administration of interstitial catheters using the Utrecht applicator allows for proper positioning into parametrial disease. These implants are tolerated well and can be performed safely in an outpatient setting, obviating the need for placing interstitial needles in the operating room without 3-D image guidance.