The treatment landscape for localized and regional prostate cancer includes active surveillance, radiation therapy (RT), and radical prostatectomy (RP). Population-based studies comparing RP to radiation reveal conflicting results due to methodological flaws. This systematic review and pooled analysis of studies aim to compare cause-specific survival (CSS), overall survival (OS), disease-free survival (DFS) and toxicity outcomes, comparing RP to RT in the management of prostate cancer. This systematic review search included the PubMed, Embase, and Cochrane libraries according to the PRISMA statement with the inception of each database up to June 24, 2023. Randomized phase 2 or 3 clinical trials that compared RP to RT in prostate cancer were included. The forest plot for the Odds ratio (OR) was plotted using the Mantel-Haenszel method, and the Z test was used to assess significance. A fixed effects model was used for meta-analysis. The search yielded seven completed randomized clinical trials and four ongoing trials. The majority of complete trials had low to intermediate-risk patient populations. OR for OS was 1.00 with 95% CI, 0.71-1.41 (P-value: 0.98), CSS OR was 0.99 with 95% CI, 0.45-2.18 (P-value 0.11), OR for DFS was 1.26 with 95% CI, 0.89-1.78 (P-value 0.19) when comparing RP to RT. The rate of distant metastatic disease was 2.3% in the RP versus 2.9% in the RT at 10 years. The rate of second malignant neoplasms was 4.5% in the RP compared to 4.2% in the RT arm at 10 years. RP caused more urinary symptoms, with a predominance of the need for urinary pads and a higher incidence of sexual dysfunction, and RT caused a higher incidence of bowel symptoms, such as blood in stools and fecal incontinence. This study provides evidence that the treatment-related outcomes are similar in patients with low to intermediate-risk prostate cancer when comparing RP to RT. Multidisciplinary treatment approaches and factoring patients' values and preferences should form the cornerstone of the ideal treatment option for each patient with localized prostate cancer. Patients with prostate cancer have an equal chance of being cancer-free and alive at 10 years with either RP or RT. In terms of side effects, RP causes more urine leakage and loss of erections, whereas RT tends to cause more bowel side effects, such as blood in stools and fecal leakage.

Purpose/Objective(s) A third of patients with biochemical recurrence (BCR) after radiation (RT) have intraprostatic radiorecurrence (IPR) on PSMA PET/CT. Patients with IPR have worse metastasis-free survival (MFS) - a surrogate for progression to lethal prostate cancer (pCa). There are limited prospective data on the best management of this growing population. We hypothesized that a dose-escalated focal salvage high dose rate (HDR) brachytherapy approach to treat IPR would be safe and effective. Materials/Methods F-SHARP is a multi-institutional phase I/II trial of focal dose-escalated salvage HDR for IPR conducted at 3 centers. Eligibility criteria included a history of localized pCa treated with any form of definitive RT, and biopsy-proven IPR with no regional or distant metastasis. All patients had a PET/CT. Patients received up to 30 Gy in 1-2 fractions (Fx) to a focal target, prioritizing OAR constraints. The primary objective was to determine the acute RT-related grade ≥3 CTCAE v4.03 GU and GI toxicity rates. Secondary endpoints included all-grade acute and late toxicity, QoL (IPSS and EPIC-26), and biochemical/radiographic disease control and survival measures. Generalized estimating equations were used for toxicity and QoL analyses. The Kaplan-Meier method was used to estimate PSA-relapse-free survival (PSA-RFS), radiographic progression-free survival (rPFS), and MFS. Cox proportional hazards models were used for univariable and multivariable analyses. Results From 2017-2023, 62 patients were enrolled. Prior RT included conventional/hypofractionated photons (60%), LDR (24%), protons (11%), and SBRT (3%). Median BCR PSA was 4.7 ng/mL (Range: 2.2-20.3) and time from prior RT was 8 years (Range: 1.4-26.5). Median tumor D98 was 23 Gy (IQR: 20-27), for 1 Fx (n = 24) and 32 Gy (IQR: 30-34) for 2 Fx (n = 38). 5 patients had concurrent hormone therapy (HT). Median follow-up was 26.1 months (95% CI = 21-36). There were no grade ≥3 acute or late toxicities. Acute/late grade 2 GU toxicity occurred in 58%/63%. Acute/late grade 2 GI toxicity occurred in 2%/3%. Acute/late grade 2 sexual toxicity occurred in 16%/32%. The table shows the proportions of patients with a minimal clinically important decline in each QoL measure. There was no difference between 1 and 2 Fx for the risk of toxicity or worsening QoL (all p > 0.05). 3-year PSA-RFS was 59%, rPFS was 65%, and MFS was 91%. 5 patients required palliative HT. There was no difference between 1 and 2 Fx for any of these events (all P > .05). Patients with PSA ≥10 ng/mL were more likely to experience any event (HR = 3.9, 95% CI = 1.2 to 12.2; P = .02). Conclusion Re-irradiation is a growing indication for RT in pCa. Dose-escalated focal salvage HDR is safe and has encouraging early efficacy. At this time, there is no difference in efficacy or toxicity between 1 vs. 2 Fx. Investigations into clinical/transcriptomic prognostic factors and patterns of failure are ongoing.

Although mpMRI and PET/CT are valuable tools for identifying LRR and delineating the extent of prostate/SV involvement, a thorough biopsy is mandatory if pursuing focal SLT. Such treatment should optimally be performed on a clinical trial with robust integration of all imaging and histopathologic data.

Purpose/Objective(s) Molecular imaging enables improved understanding of the anatomic regions involved with metastatic prostate cancer (PC) due to the improved sensitivity compared to conventional imaging. Consequently, there is increasing awareness that PC metastasizes relatively frequently to the para-aortic (PA) lymph node region, compelling some radiation oncologists to electively cover this area if it is determined to be at high risk or if nodes are already involved. However, the optimal contouring boundaries are unknown. The objective of this study is to use molecular imaging to develop guidelines for contouring the PA clinical target volume (CTV) in patients with PC. Materials/Methods We conducted a retrospective cohort study of patients with PC undergoing 18F-fluciclovine (FLU) or 18F-DCFPyL PSMA PET/CT at our institution. Images of patients with PET-positive PA lymph node involvement were imported into the treatment planning system and the avid nodes were contoured. The radial distance from the epicenter of each node was measured in all dimensions relative to the inferior vena cava and aorta, and superiorly relative to the left renal vein. The PA CTV was delineated per the 2021 NRG/RTOG post-operative endometrial/cervical cancer atlas, as principles of these malignancies are frequently used to delineate this region. Descriptive statistics were used to assess the performance of this gynecologic atlas and generate recommendations for contouring in PC patients. Results 246 men had molecular PET imaging at our institution from 10/2016 to 1/2022 (48% FLU, 52% PSMA). 31 men (13%) had evidence of PA nodal metastasis. In these patients, 16% had de novo, 52% recurrent, and 32% castration-resistant metastatic PC. The median number of positive PA lymph nodes per patient was 1 (IQR 1-3.5). The distance from central vasculature and left renal vein are shown in the Table. Only 66% of PA nodes were covered using the left renal vein as the superior border and 75% were covered using 1.5 cm above the left renal vein. Overall, the gynecologic atlas missed 25% of nodes (57% due to left sided and 30% due to superior misses), suggesting unique target delineation should be considered for PC patients. We recommend expanding the PC PA CTV in the left lateral and superior dimensions, with detailed recommendations to be included in our presentation. Conclusion We used molecular PET imaging to determine the anatomic patterns of PA metastasis to develop contouring guidelines for creating a PA CTV in patients with PC. Although the optimal patient selection and clinical benefits of PA RT remain uncertain, our results will aid in delineating the optimal target and are currently being validated in an independent dataset. Table. Distance from central vasculature and left renal vein (cm)

Transcription factor HIF-2α is an established oncogenic driver, and its activation in VHL disease is caused by germline alterations in the VHL gene. Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease who require therapy for associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery. Results with more than 3 years of follow-up from the phase 2 LITESPARK-004 study (NCT03401788) are presented. Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, no prior systemic anticancer therapy, and ECOG PS 0-1 were eligible to receive oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was ORR in VHL disease–associated RCC per RECIST v1.1. Secondary endpoints were ORR in other VHL disease–associated neoplasms, TTR, DOR, and safety. As of April 1, 2022, 38 of 61 pts (62%) remain on treatment; primary reasons for treatment discontinuation were pt decision (n = 11; 18%) and disease progression (n = 6; 10%). Median follow-up was 37.8 mo (range, 36.1-46.1 mo). Of 61 pts with RCC, ORR was 64% (95% CI 50.6-75.8; 4 CRs, 35 PRs). Median TTR was 11.1 mo (range, 2.7-30.5 mo), and median DOR was not reached (range, 5.4+ to 35.8+ mo). Of 22 pts with pNET, ORR was 91% (95% CI 70.8-98.9; 7 CRs, 13 PRs); median DOR was not reached (range, 11.0+ to 37.3+ mo). Of 50 pts with CNS hemangioblastomas, ORR was 44% (95% CI 30.0-58.7; 4 CRs, 18 PRs); median DOR was not reached (range, 3.7+ to 38.7+ mo). Of 16 evaluable eyes in 12 pts with retinal hemangioblastomas, 100% showed improvement. Grade 3 treatment-related AEs (TRAEs) occurred in 18% of pts (n = 11); anemia was most common (n = 7; 11%). No grade 4 or 5 TRAEs occurred. No new safety findings were observed with additional follow-up. With a median follow-up of 37.8 mo, belzutifan continues to demonstrate clinically meaningful antitumor activity and durable responses in VHL disease–associated RCC, pNET, and CNS and retinal hemangioblastomas, with a manageable safety profile.

Purpose/Objective(s)Low dose radiation (LDR) may have paradoxically beneficial effects via an adaptive response. We aimed to assess the adaptive response of healthy and malignant skin tissue to low doses of radiation and explore the molecular details behind the induced adaptive response.Materials/MethodsWe conducted a prospective, randomized pilot study (N=8) to ascertain the biological effects of integrating 0.1 Gy of LDR into standard radiotherapy sessions (2.0 Gy fractions) over the first two weeks of radiotherapy for patients 18-80 years of age (both sexes) diagnosed with squamous cell carcinoma of skin (lesions of 1 – 10 cm). Radiation treatment was done with a linear accelerator. The patients received definitive radiation for the tumor as determined by the treating physician using 2.0 Gy fractions. In addition, 0.1 Gy of LDR was integrated into the standard radiotherapy course on day 0 and day 6 over the first two weeks of treatment. Radiation delivery to healthy tissue was with a 1.5 cm margin around the tumor using a mask over the tumor. We obtained partial thickness skin biopsy samples of the tumor and peri-tumoral normal tissue before treatment from four patients (for control). An additional four patients (actively treated) were biopsied before and 24 hours after 0.1 Gy of LDR (day 0, 1 and day 6, 7). RNA was obtained from skin biopsies and processed for genetic expression (138K genes).ResultsThe change in gene expression in healthy peri-tumoral tissues due to LDR exposure was relatively low (only 325 genes: 170 upregulated, 155 downregulated). The senescence and autophagy in cancer and genotoxicity pathway genes showed the most significant downregulation in peritumoral healthy tissue comparing days 0 and 1. The biological pathways in peritumoral healthy tissue comparing days 6 and 7 showed predominantly downregulation of genes with most pronounced downregulation seen in electron transport chain in mitochondria and genes involved in non-alcoholic fatty liver disease. In contrast to normal peritumoral tissue, the difference in gene expression in tumor tissue due to LDR exposure was significantly more pronounced (5,651 genes: 2,896 upregulated, 2,755 downregulated) The allograft rejection genes and nuclear receptor meta-pathway were the most upregulated in the tumoral tissues comparing days 0 and 1. The nuclear receptor meta-pathway were the most upregulated in the tumoral tissues on days 6 and 7. The Allograft rejection pathway in skin cancer was among those upregulated.ConclusionLDR had a modest effect on miRNA expression when applied to healthy peritumoral skin. Downregulated pathways predominate, and DNA repair mechanisms are stimulated by the first dose in healthy tissue. In contrast, a more pronounced effect on gene expression (as measured by miRNA profiles), including upregulation of several key relevant pathways, was induced by LDR to malignant tissue.

Purpose/Objective(s)Salvage local therapy (SLT) with brachytherapy or SBRT for local radiorecurrence (LRR) of prostate cancer after prior radiotherapy (RT) is increasingly being used due to growing data demonstrating the safety and efficacy of SLT, as well as the availability of advanced imaging to identify LRR, such as multiparametric MRI (mpMRI) and molecular PET imaging (18F-fluciclovine or 18F-DCFPyL PSMA). Further, advanced imaging has led to investigation into focal SLT to improve the therapeutic ratio of reirradiation. Yet, data are limited on the ability of mpMRI and PET to detect LRR and how well they localize the area(s) of recurrence in the prostate to guide focal SLT. Our objective was to determine the ability of mpMRI and PET imaging to detect the presence and full extent of the areas of involvement in men with LRR.Materials/MethodsWe conducted a cohort study of men with LRR of prostate cancer enrolled in the FSHARP phase I/II trial of salvage focal HDR brachytherapy at our institution. Workup included PET/CT, mpMRI of the prostate, and a biopsy documenting the LRR prior to enrollment. Descriptive statistics were used to compare mpMRI and PET detection and localization with biopsy findings to determine the sensitivity/false negative rate (FNR) of each imaging modality, and the frequency with which biopsy reveals disease that would have been missed if the imaging abnormality alone was used to define the focal salvage HDR target.ResultsA total of 40 men were included in this analysis. Median age was 70.5 yrs (Range: 58-83). Median time from initial RT was 9.5 yrs (2-28). Initial NCCN risk groups were as follow: 13 had low risk, 21 had intermediate risk and 2 had high risk. 26 were treated with conventionally fractionated photon RT, 7 with LDR brachytherapy, 4 with protons, 2 with SBRT and 1 with neutron therapy. Regarding recurrence biopsy, 24 men had MRI/TRUS fusion biopsy and 16 had TRUS biopsy alone. A median of 14 cores were obtained and a median of 6 cores were positive. Gleason grade grouping (GG) was as follows: 1 had GG 1, 11 had GG 2, 12 had GG 3, 6 had GG 4, and 4 had GG 5. The median number of MRI target lesions was 1 (0-4), and the median number of lesions on PET was 1 (0-2). 38 men had fluciclovine and 2 had PSMA PET. The table depicts the sensitivity and FNR of each imaging modality, and frequency of pathologically identified disease outside of the imaging target.ConclusionOur study emphasizes that though mpMRI and PET are valuable tools for restaging and target volume delineation in LRR of prostate cancer, there are limitations to their use. These imaging modalities cannot be relied upon alone if pursuing focal salvage due to a high FNR, and because the full extent of disease is rarely identified, leading to the risk of marginal misses.

The gut microbiome of cancer patients impacts response to Immune Checkpoint Inhibitor (ICI) therapy. However, neither which bacteria, nor their mechanism of influence on immunotherapy are yet well characterised. Microbiotica's precision microbiome profiling of melanoma patients recruited to the MelResist (Cambridge, UK) study has identified a consortium of 9 diverse bacteria, including 4 novel species, which correlate with immune checkpoint inhibitor response across multiple published melanoma cohorts. This consortium, MB097 is being developed as an anti-PD1 co-therapy for melanoma patients. We are working to understand how the bacteria interact with the immune system to influence ICI response. Human monocyte-derived dendritic cells were incubated with live bacteria (individually or as a consortium) firstly anaerobically, then aerobically. The stimulated dendritic cells were also used to activate primary allogenic Cytotoxic T lymphocytes (CTL) and NK cells. CTL and NK activation was assessed by intracellular FACS and tumour cell (SKOV3). MB097 bacteria, individually or as a consortium, strongly activated dendritic cells, upregulating maturation markers CD83 and CD86. Importantly, the strains were more potent inducers of IL-12 than IL-10 (up to 30-fold higher) resulting in a higher IL-12:IL10 ratio than other stimuli, LPS, PolyI:C and other bacteria. These bacteria-stimulated dendritic cells triggered Cytotoxic T Lymphocytes to upregulate Granzyme B, Perforin and IFNg, and kill tumour cells. The MB097 strains stimulated dendritic cells triggered NK cells to release IFNg release and kill tumour cells. MB097 is a consortium of bacteria strongly linked to ICI response across multiple published series. In vitro, the bacteria activated dendritic cells, which in turn activated CTLs and NK cells. Interesting, the bacteria that most potently induced CTL activation triggered the highest IL-12 to IL-10 ratio from dendritic cells. This included 3 novel species. This IL-12 axis was less tightly linked to NK cell activation, suggesting other as yet undefined mechanisms may influence these cells.

We have developed a process to efficiently provide LD-WTRT for patients with COVID pneumonia that minimizes staff exposure, departmental equipment, and room contamination. Should clinical trials indicate that LD-WTRT helps treat COVID pneumonia patients, this process can work in most hospital-based radiation oncology departments to provide LD-WTRT efficiently and safely. Staff and cancer patient vaccination will further lower the risks of implementing LD-WTRT but is not necessary with careful planning and consultation with infection control.

BACKGROUND:Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS:Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS:One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS:Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

To prospectively assess the quality of life (QOL) in patients with clinically diagnosed early-stage lung cancer undergoing definitive stereotactic body radiation therapy (SBRT). We enrolled medically inoperable, clinically diagnosed T1-3N0M0 lung cancer patients without a confirmed pathologic diagnosis. Reasons for lack of pathologic confirmation included high risk of biopsy-related complications, prior non-diagnostic biopsy, or patient refusal. Patients were diagnosed based on ≥85% risk of malignancy using Herder et al PET-based prediction model estimate or consensus recommendation from thoracic multidisciplinary tumor board. QOL was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30) and Lung Cancer-13 questionnaires (QLQ-LC13). QOL scores were measured at baseline, 3 months, 6 months, 1 year, and 2 years. A clinically meaningful change in QOL was defined as an increase or decrease in 10 points relative to the baseline, which has been previously validated to correspond to 'moderate' or 'very much' change by Osaba et al, 1998. Patients who developed disease progression were excluded from the QOL analysis after disease progression for risk of competing decline in QOL. Linear mixed-effects model was utilized to evaluate change in QOL scores over time. From 2016-2019, 43 patients were enrolled. Median follow-up is 11.0 months (IQR 6.0-26.1). Mean age was 74.2 years ± 8.3. Mean Charlson Comorbidity Index was 5.5 ±1.8. Compliance rate with QOL was 84.3%. QLQ-C30 scores for global health, functioning scales, and select QLQ-C30 and QLQ-LC13 symptom scores are shown in the Table. There was no significant change in global health/QOL at any time. Regarding the functional scales, there was improvement in social functioning at 1 and 2 years compared to baseline but without statistical significance. There were no significant differences in any of the functional scales at any time point. There was transient worsening in cough at 1 year, which returned to baseline at 2 years. There were no significant differences in any of the symptom scales at any time point otherwise. In medically inoperable patients with clinically diagnosed early stage lung cancer treated with SBRT, QOL was preserved without significant decline in global health, functional domains, or symptoms in this first planned analysis early in follow up. Longer follow up will be required to confirm these results.Abstract 2489; TableQOL scores.Baseline3 month6 month1 year2 yearp-valueGlobal Health63 ± 2265 ± 2257 ± 2967 ± 1657 ± 260.31Physical functioning62 ± 2464 ± 2559 ± 2761 ± 2059 ± 220.76Role functioning64 ± 3172 ± 3167 ± 3572 ± 3269 ± 330.87Emotional functioning72 ± 2175 ± 2376 ± 2778 ± 2873 ± 250.68Cognitive functioning81 ± 2373 ± 2978 ± 2581 ± 2676 ± 250.12Social functioning71 ± 3480 ± 2776 ± 2883 ± 2585 ± 180.70Fatigue36 ± 2238 ± 2639 ± 2733 ± 2432 ± 190.93Coughing36 ± 2933 ± 2436 ± 2949 ± 3141 ± 220.35Dyspnea34 ± 2635 ± 2537 ± 2933 ± 2337 ± 240.92 Open table in a new tab

Astronauts are exposed to a wide variety of stressors ranging from radiation and microgravity to persistent fluids shifts, circadian shifts and the psychological stress of prolonged isolation and confinement. On deep space missions, beyond the range of the Earth's magnetosphere, ionizing radiation may increase oxidative stress and DNA damage, immune system dysregulation and alter the effectiveness of the cellular defense mechanisms. By reviewing the health problems reported by astronauts participated in previous space missions, it is evident that viral infections are not rare in space. Recent reports suggest that COVID-19 can last for a long time in communities. Although NASA implements countermeasures designed to limit crew illness during space missions such as a pre-flight quarantine, it is not clear whether an outbreak can be prevented. Currently, it is not likely that astronauts could get a viral infection, but the consequences of potential life-threatening viral diseases such as COVID-19 should be better characterized. In this paper we discuss why COVID-19 fatality in space might be significantly higher than on the Earth. The reasons for such an increased risk include 1) uselessness of social distancing due to microgravity 2) immune system dysregulation 3) possibly higher mutation rates of RNA viruses such as the novel coronavirus (SARS-CoV-2) 4) existence of strong selective pressure and 5) decreased maximum oxygen uptake. Given these considerations, the combined effects of microgravity, space radiation (and possibly other major space stressors) on the immune system of astronauts exposed to SARS-CoV-2 and possible interactions of the virus, space stressors and host should be carefully investigated.

The autosomal dominant hereditary disorder VHL disease is characterized by germline inactivating mutations in the VHL gene and constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, was evaluated for efficacy for treatment of VHL-associated tumors in this open-label phase II study (NCT03401788).

IrAEs typically occur within 4 months of starting anti-PD1-based therapy (anti-PD1 +/- anti-CTLA4), but there are isolated reports of delayed irAEs (onset >12 months after commencement). This study describes the incidence, nature and management of delayed irAE in melanoma patients (pts).

Background MEDI0680 is a humanised IgG4κ anti-programmed cell death-1 (PD-1) mAb. We hypothesised that simultaneous blockade of PD-1:PD-L1/PD-L2 with MEDI0680 (M) and PD-1:PD-L1/CD80 with anti-PD-L1 mAb durvalumab (D) would improve efficacy vs blockade of the PD-1:PD-L1/PD-L2 pathway (with nivolumab; N) alone. M+D was well tolerated in the dose-escalation phase of a Phase I/II study in pts with advanced solid tumours, with an ORR of 33% (10/30; including 3/4 RCC pts). In the Phase II portion of the study, we compared M+D to N in a dose-expansion cohort of pretreated, immunotherapy (IO)-naive pts with metastatic ccRCC. Methods Eligible pts had received 1–3 prior therapy lines, no prior IO exposure and ≥1 measurable lesion. They were randomised 2:1 (stratified by MSKCC risk group and PD-L1 expression) to M 20 mg/kg IV + D 750 mg Q2W or N 240 mg IV Q2W until unacceptable toxicity or disease progression, for ≤2 years. Endpoints included investigator-assessed ORR by RECIST v1.1 (primary endpoint), PFS and safety (secondary). Sample size was ∼60 to detect a difference of 26.0% (ie, ORR = 47.5%, assuming ORR of 21.5% for N) with 76% power at a 1-sided significance level of 0.10. Results By Feb 24, 2019, 63 pts were randomised. Baseline pt/disease characteristics were generally well balanced, but more pts on N had favourable MSKCC risk (7/21; 33.3%) vs M+D (10/42; 23.8%). ORR was 14.3% (6/42; 2 CR, 4 PR; plus 2 unconfirmed PR) vs 19.0% (4/21; 4 PR, 0 unconfirmed) for M+D and N, respectively. There was no difference between arms in ORR by PD-L1 expression ( Conclusions Efficacy was similar with combined M+D and N monotherapy in pts with TKI-pretreated, IO-naive, metastatic ccRCC, but more pts discontinued M+D due to TRAEs. Clinical trial identification NCT02118337. Editorial acknowledgement Aaron Korpal, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure M.H. Voss: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Honoraria (self): Eisai; Honoraria (self): Exelixis; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Calithera; Honoraria (self): Corvus. A.A. Azad: Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Research grant / Funding (institution), Non-remunerated activity/ies: Merck Serono; Honoraria (self), Advisory / Consultancy: Tolmar; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy: Telix Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Sanofi. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Triptych Health Partners; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Epic Sciences; Research grant / Funding (institution): BMS; Research grant / Funding (institution): BI; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Novartis. I. Achour: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H. Hu: Full / Part-time employment: AstraZeneca. L. Lewis: Travel / Accommodation / Expenses, Full / Part-time employment: AstraZeneca. F.L. Walcott: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.F. Oosting: Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

The purpose of these developments is to establish an Advanced Ion Therapy Research Center in the US. The proposed center will be the first linac-based ion therapy facility in the world, with the advantage of much desired fast energy and ion beam species switching capability. Such a facility would prove a unique platform to stage the development of pre-clinical studies to prepare for FDA clearance for carbon and other ion beam therapies in the US, and pave the way to establishing clinical ion therapy facilities in this country. The proposed center will enable a breadth of research and applications such as cellular radiobiology, comparative studies of different ion beam therapies and the development of real-time imaging for precise and accurate dose delivery. A multi-institutional collaboration is proposing an innovative center for ion therapy research that will combine an advanced compact carbon ion linac, a compact superconducting carbon beam gantry and real-time MRI-guided beam delivery for therapy. Research and Development towards the realization of the proposed center is underway along three major axes. First, the development of high-gradient accelerating structures for the linac, second, the development of compact curved, combined-function bending magnets and beam scanning magnets for the gantry, and third, the development to combine real-time MRI imaging with ion beam delivery systems. A conceptual design for a compact carbon ion therapy linac has been recently developed. The linac is 45 meters long and capable of accelerating ion beams from proton to neon up to an energy of 450 MeV/u. Prototypes of high-gradient accelerating structures required for the linac are being fabricated and tested. A design of a compact superconducting carbon gantry was also developed and a compact carbon beam scanner magnet is being prototyped. A preliminary concept for MRI-guided ion beam delivery was most recently developed. Other imaging options and range verification techniques, including prompt gamma, positron emission tomography, ionoacoustics and ion beam CT are being considered. Progress made in these areas of development will be presented. Linac-based technology for ion therapy allows more flexibility in beam tuning than synchrotron-based technology with much faster energy modulation and ion beam switching. The reported developments will enable this technology and pave the way to establishing the proposed therapy research center as a national and international resource.

The dosimetric advantage of treatment with proton beam therapy shows tremendous clinical promise. In proton treatment planning, kV CT images are converted using the stoichiometric method to obtain a model of the relative stopping powers (RSP) of the patient’s tissues. This process has inherent errors in accurately predicting the RSP values within the patient. To ensure target coverage in the presence of these uncertainties, additional margins are added to a proton field resulting in unwanted dose to healthy tissues. Several studies have systematically evaluated the magnitude of range calculation uncertainties when using kV CT imaging, with each yielding similar recommendations. In this study, we used the identical evaluation methods to calculate the potential range uncertainty if the patient model was obtained via direct proton transmission tomography (pCT) rather than kV X-ray imaging. pCT images of a phantom designed with materials of known RSP were obtained and reconstructed using a most likely path length method. The accuracy of the reconstructed images in predicting the RSP varied from 0.1% up to 0.8% for different materials. Using these uncertainties in the pCT images, evaluations for uncertainty margins were made using the identical method as in prior studies. An attempt was made to quantify potential reductions in range uncertainty in a case where pCT is used for the patient model. Table 1 summarizes the potential reduction in range uncertainty margins if pCT images were used to obtain the RSP distributions and compared to RSP distributions obtained using the stoichiometric method from prior studies. Results show that if the error evaluation methods used in the prior studies are re-evaluated using the reported errors of the pCT phantom images, considerable reductions in range uncertainty margins could be obtained.Abstract 3752Tissue TypeRange Error with kV CTRange Error with Proton CTConfidence LevelCommentsMoyers (2010)Soft Tissue3.5%1.4%2.0 SigmaCurrent TechnologySoft Tissue2.2%0.9%2.0 SigmaWith Dual Energy CT and MCYang (2012)Lung5.0%1.0%1.0 SigmaSoft Tissue1.6%0.5%1.0 SigmaBone2.4%0.6%1.0 SigmaPagganetti (2012)4.6%4.0%1.5 SigmaLocal Inhomogeneities2.4%1.4%1.5 SigmaLocal Inhomogeneities w/ MC Open table in a new tab The use of pCT images for modeling the RSP of proton therapy patients will considerably reduce the magnitude of the margins needed to account for proton range uncertainty. With the clinical implementation of more advanced proton delivery, especially multi field optimization methods, the reduction of range uncertainty has become even more critical. Further development in the clinical implementation of pCT in proton therapy departments would greatly benefit proton patients.

Proton radiography enables proton range verification in addition to the anatomical alignment verification currently obtained with x-ray radiography. Design specifications require that a clinical system be simple, lightweight, easily scaled to large field sizes, operate at high speed to maximize patient throughput, and expose the patient to the minimum possible radiation dose for a given resolution. We are developing a system to produce images of proton stopping power by tracking individual protons proximal and distal to the patient and then measuring the proton residual range after traversing the patient. Due to multiple scattering effects, each proton deviates randomly from its projected trajectory. To achieve optimal spatial resolution, an image reconstruction algorithm must fully exploit the individual three-dimensional proton position information. We have developed an iterative algorithm for radiography that fully exploits proton path information to produce projective radiographs with no blurring from multiple scattering. Simulations of our detector design, with and without multiple scattering effects included, determine the expected accuracy of our proton path reconstruction, and the impact on the spatial resolution of the reconstructed image. Tests of our detector components with proton beams demonstrate the performance needed to validate our simulations. Protons typically scatter transversely from the projected path by 4 mm after 20 cm of water. Our simulations demonstrate path reconstruction of individual protons to better than 1 mm. Our iterative algorithm successfully produces images with 1 mm sharpness. The iterative process necessarily increases pixel noise compared to estimates neglecting multiple scattering and additional protons will be needed to achieve a given contrast. Operation of our detector components in a test beam demonstrates the required proton tracking resolution and efficiency to optimize resolution and minimize dose to the patient. A proton radiography system optimizing image sharpness and dose to the patient will individually track protons before and after the patient. An iterative algorithm produces images with spatial resolution given by the tracking accuracy, at the price of increased pixel noise. We are in the process of integrating the necessary components into a fully functional system.