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Purpose: Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. Methods and materials: Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33–0.63 Gy/s field dose rate, 244 MeV) or FLASH (71–89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40–60 Gy (8–14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation.Results: TCD50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0–51.4) Gy for CONV and 51.3 (48.6–54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD50 (dose for 50% of mice displaying moist desquamation) of Conclusions: FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.

Reirradiation and irradiation of sarcoma is often difficult due to the frequent need for a high dose of radiation in order to increase tumor control. This can result in a greater risk of toxicity which can be mitigated with the use of proton therapy. The present review aims to summarize the role of proton therapy in these 2 clinical contexts.

Photothermal therapy (PTT) has emerged as a promising therapeutic approach for tumor control and ablation. Attention has focused on exploring advanced organic photothermal agents (OPTAs), with advantages of easy modification, adjustable photophysical and photochemical properties, good compatibility, and inherent biodegradability. However, few detailed studies on how to maximally channelize nonradiative heat generation from the viewpoint of the photothermal conversion mechanism have been reported. Thus, here we assimilate and elaborate on several available action mechanisms to maximize the photothermal conversion efficiency (PCE) of organic dyes. Moreover, we also propose several potential challenges that require substantial future work to address.

Radiation is a known immune modulator that drives both local and systemic immunologic effects. There is increasing interest and investigation into harnessing the pro-immunogenic effects of radiation for patients with metastatic cancer to improve systemic disease control and clinical outcomes. Here, we review fundamental immunology concepts in the context of our current understanding of both the pro-immunogenic and the less well-appreciated immunosuppressive effects of radiation therapy. Our aim is to offer the radiation oncology community a lens into the progress the field has made understanding the complex interaction between tumor-directed irradiation and immune-mediated tumor control, thus promoting further discovery and translation of radio-immuno-oncology innovation.

PURPOSE: We sought to investigate the tumor control probability (TCP) of vestibular schwannomas (VS) following single-fraction stereotactic radiosurgery (SRS) or hypofractionated SRS over 2–5 fractions (fSRS). MATERIALS AND METHODS: Studies (PubMed Indexed from 1993 – 2017) were eligible for data extraction if they contained dosimetric details of SRS/fSRS correlated with local tumor control. The rate of tumor control at 5 years (or at 3 years if 5-year data were not available) were collated. Poisson modeling estimated the TCP per equivalent dose in 2 Gy per fraction (EQD2) and in 1, 3, and 5 fractions. RESULTS: Data were extracted from 35 publications containing a total of 5162 patients. TCP modeling was limited by the absence of analyzable data of

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with

Purpose Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. Methods and Materials A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/β= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. Results After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. Conclusions Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models.

Juvenile nasopharyngeal angiofibromas (JNAs) are a rare, highly vascular benign tumor affecting adolescent males. Recent advances in endoscopic visualization and technique have allowed for complete extirpation of these tumors endoscopically. Proponents of this approach find benefit in the lack of facial incisions, decreased intraoperative blood loss, and excellent tumor control. This chapter describes the endoscopic approach to JNAs.

Application of radiosurgery to the newly diagnosed or post-operative residual perioptic lesions has been proved to improve tumor control. However, risk of vision injury induced by radiosurgery may increase substantially if the radiation dose is too high or tumor is close to the optic apparatus. The purpose of this study was to evaluate the safety and the effectiveness of fractionated stereotactic radiosurgery (FSRS) for perioptic tumors. We retrospectively analyzed 60 consecutive patients with 53 meningiomas and 7 schwannomas treated with FSRS between October 2007 and February 2020. We administered a marginal dose of 6–7 Gy (mean 6.8 Gy) per fraction and delivered 3 fractions in 3 consecutive days. The median tumor volume was 6.31 cm3 (range 0.3–58.23 cm3). The mean minimum lesion-optic distance (MLOD) is 0.85 mm (range 0–3 mm). After mean follow-up period of 69.6 months (range 6.82–156.32 months; median 58.9 months), the tumor control rates at 1, 3, 5, 8 and 13 years were 98.3%, 93.4%, 90.60%, 88.4% and 88.4%, respectively. Four out of the 60 tumors (6.7%) experienced a transient volume increase after FSRS. None of the patients developed visual impairment related to radiation induced optic neuropathy (RION) after FSRS. In conclusion, FSRS offers an alternative treatment option in treating perioptic meningiomas and schwannomas with acceptable tumor control rates and good visual preservation in the present study.

Purpose Although consensus guidelines for postresection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of postresection SRS for deep brain metastases based on whether or not the surgical corridor was targeted. Materials and Methods We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only “deep” tumors (defined as located ≥1.0 cm from the pial surface before resection). Results In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12 months for targeting versus not targeting the corridor, respectively, for overall local failure 2% (95% confidence interval [CI], 0%-11%) versus 9% (95% CI, 1%-25%; P = .25), corridor failure 0% (95% CI, 0%-0%) versus 9% (95% CI, 1%-25%; P = .06), cavity failure 2% (95% CI, 0%-11%) versus 0% (95% CI, 0%-0%; P = .91), and adverse radiation effect 5% (95% CI, 1%-15%) versus 13% (95% CI, 3%-30%; P = .22). Leptomeningeal disease (7%; 95% CI, 2%-18%) versus 26% (95% CI, 10%-45%; P = .03) was higher in those without the corridor targeted. Conclusions Omitting the surgical corridor in postoperative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of postresection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

Purpose To evaluate the long-term follow-up of recurrent conjunctival and corneal intraepithelial neoplasia (CCIN) treated with combination topical interferon alfa-2b and retinoic acid (I/RA). Methods Our study represents a retrospective observational interventional series of 82 eyes from 82 patients from a single institution, reviewed for CCIN. All were administered topical interferon alfa-2b 1 million IU/mL QID and retinoic acid 0.01% every other day. Patients had been diagnosed by biopsy. A Kaplan-Meier survival analysis, Wilcoxon signed-rank test and a multivariate logistic regression were statistical tests used to correlate recurrence with patient and tumor variables. Results 79 eyes assessed for CCIN diagnoses and treated with I/RA achieved tumor resolution. The median tumor-free follow-up was ~109.1 months with a median time to resolution being ~2.8 months. Our median treatment duration was ~11.3 months. The greatest difference in the mean total residual tumor size was identified between Months 0–1 [-7.63 mm2]. The difference in mean total residual tumor size remained significant till 36-months. A statistically significant correlation with recurrence was identified for biopsy type [OR 0.138]. 6 patients experienced papillary conjunctivitis which resolved with dosage reduction. Conclusions Combination I/RA was effective in treating CCIN lesions with few transient side effects. The combination of retinoids and interferons may represent a viable topical therapeutic agent with an extended tumor-free follow-up and a large proportion of our study's patients achieving >10 year's tumor-free follow-up. Our treatment duration is long, but by cost-comparing surgical against medical interventions, topical I/RA may serve as a safe and effective alternative.

Objective Atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment. These diseases are difficult to definitively treat with traditional radiotherapy without injuring adjacent brain parenchyma. The physical properties of ion radiotherapy allows for treatment plans that avoid damaging critical neural structures. The objectives of this systematic review were to evaluate the use and efficacy of ion radiotherapy in the treatment of atypical and anaplastic meningiomas. Methods We performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion radiotherapy in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas. The outcome of interest was rate of local tumor control at 5 years after ion radiotherapy. Results Across the included studies, proton therapy delivered a mean local control rate of 59.62% after 5 years. Carbon ion radiotherapy studies showed local control rates of 95% and 63% at 2 years for grade II and III meningiomas, respectively. In contrast, carbon ion radiotherapy studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33% at 2 years. Conclusions Proton and carbon ion radiotherapy maintain comparable rates of local control to conventional photon therapy and allow for more targeted treatment plans that may limit excess radiation damage. Although additional prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas.

Using auto-planning, the dosimetric and biological differences between PET- and CT-based target delineation in LA-NSCLC were studied. Twenty-three patients with IIIA-IIIB NSCLC were included in this retrospective study. For each patient, two AP plans (Plan_PET, Plan_CT) were generated based on PET- and CT-based gross tumor volume (GTVPET, GTVCT). The volume, boundary and center of mass (COM) of GTVPET and GTVCT were compared. Dosimetric indicators such as mean lung dose (MLD) and so on were evaluated. Tumor control probability (TCP) of GTVPET and GTVCT and normal tissue complication probability (NTCP) of total lung and heart were calculated. A paired-samples t-test was used to check for significant differences (p

Objective We evaluated the tumor control and cranial nerve (CN) outcomes after adjuvant stereotactic radiosurgery (SRS) for petroclival, cavernous sinus, and cerebellopontine angle meningiomas. Methods From our prospectively maintained database of 2022 patients with meningioma who had undergone Leksell SRS during a 30-year interval, we found 43 patients with petroclival, 94 with cavernous sinus, and 13 patients with cerebellopontine angle meningiomas who had undergone adjuvant SRS after surgical resection of the meningioma. The patients included in the present report had had ≥1 CN deficit at the initial presentation and a minimum follow-up period of 12 months. The median age at SRS was 54 years (range, 22–81). SRS was performed for residual tumor in 104 patients (69%) and recurrent tumor in 46 patients (31%). The median tumor volume treated with SRS was 8.1 cm3 (range, 0.3–42), and the median margin dose was 13 Gy (range, 10–20). Results Tumor control was achieved in 135 patients (90%) at a median follow-up point of 75 months. The progression-free survival rate after SRS was 99.5% at 1 year, 98% at 3 years, 95% at 5 years, and 90% at 10 years. Overall, 29 of the 150 patients (19%) reported improvement in CN function. Deterioration in CN function after SRS developed in 15 patients (10%). The rate of deterioration was 3.5% at 1 year, 5.5% at 3 years, and 7% at 5 years. Conclusions Adjuvant SRS provides effective tumor control and a low rate of new or worsening CN deficits.

Treatment of fast-growing, human papillomavirus-negative, head and neck cancers (HNCs) remains challenging from the perspectives of both tumor control and late sequelae. In this study, we use systematic radiobiological optimization to identify fractionation schemes that markedly improve the radiotherapeutic effectiveness balance between tumor control probability (TCP) and late normal tissue complication probability (LNTCP), as compared with standard fractionation.We track the development after each treatment fraction of both tumor control and late sequelae. Toward the end of the treatment, accelerated repopulation of fast-growing HNC tumors means that further fractions minimally improve TCP but result in major LNTCP increases, providing the potential for optimization of the TCP-LNTCP balance. We used a recent improved model of accelerated repopulation, calibrated with extensive HNC clinical trials data, to identify optimally effective treatment regimens that both increase TCP and significantly decrease LNTCP. For comparison, we also used standard repopulation models.An optimized hypofractionated schedule of 18 × 3.0 Gy is predicted to substantially increase TCP, particularly for late-stage HNC tumors (eg, ∼35% to 49% for late-stage tumors) while decreasing high-grade LNTCP (eg, ∼13% to2%), as compared with a standard 35 × 2.0 Gy protocol. In addition, the treatment time is reduced from 47 to 24 days. Twice-daily treatments of 1.8 Gy per fraction provide still better outcomes. The hypofractionation predictions are robust, being almost independent of the details of the repopulation model.Hypofractionation or its close variant, accelerated hyperfractionation, efficiently overcomes tumor repopulation in fast-growing tumors and can be optimized toward the end of treatment when repopulation causes the TCP to increase only very slowly while LNTCP increases rapidly. Radiobiological modeling suggests that optimized 3.0 Gy per fraction hypofractionation (or 1.8 Gy per fraction, 2 fractions per weekday, accelerated hyperfractionation) is considerably more effective for HNC tumor control and for reduction of late effects than standard 2.0-Gy fractionation.

Purpose To evaluate the radiobiological impact of PB algorithm versus MC algorithm in intensity-modulated proton therapy (IMPT) plans for breast cancer treatment. Methods 20 breast cancer patients who received IMPT to the breast/chest wall and regional lymphatics were included in this study. For each patient, 2 IMPT plans were generated: a PB-optimized plan and a MC-optimized plan. The radiobiological and dosimetric impact to the CTV of the dose algorithms was assessed. The Poisson Linear-Quadratic model was used to estimate the tumor control probability (TCP). The influence of the model parameter uncertainties on the TCP was tested against different sets of published model parameters. Results The PB-optimized plans significantly under-dosed the target as compared to the MC-optimized plans. The median (range) differences in CTV D95% and CTV Dmean were 1.9 (1.2–3.1) Gy and 1.2 (0.5–1.9) Gy, corresponding to 3.8% (2.4−6.2%) and 2.4% (1.0−3.8%) of the prescription dose. The TCP was lower in the PB-optimized plans than the MC-optimized plans. The median (range) of the TCP differences (ΔTCP) were 4% (2−6%), 3% (2−5%), and 2% (1−3%), respectively, when calculated using 3 different model parameter sets. The ΔTCP correlated with the CTV dose difference, and moderately correlated with the CTV volume. Conclusion Due to the inaccurate dose modeling, PB-optimized plans under-dose the target and therefore yield a lower TCP compared to MC-optimized plans in breast IMPT. The magnitude of the resulting difference in TCP reached 6% in our study.

Fractionated CyberKnife radiosurgery (CKRS) treatment for acoustic neuromas may reduce the risk of long-term radiation toxicity to nearby critical structures compared to that of single-fraction radiosurgery. However, tumor control rates and clinical outcomes after CKRS for acoustic neuromas are not well described. We retrospectively reviewed all acoustic neuroma patients treated with CKRS (2004-2011) in a prospectively maintained clinical and radiographic database. Treatment failure, the need for additional surgical intervention, was evaluated using Kaplan-Meier analysis. For 119 treated patients, median values were 49 months (range, 6-133 months) of follow-up, 1.6 cm3 (range, 0.02-17 cm3) tumor volume, and 18 Gy (range, 13-25 Gy) prescribed dose delivered in 3 fractions (range, 1-5 fractions). Thirty-five of 59 patients (59%) with pre-radiosurgery serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery class A or B) maintained serviceable hearing at the last audio follow-up (median, 21 months). Two of 111 patients (2%) with facial nerve function House-Brackmann (HB) grade ≤3 progressed to HB grade >3 after radiosurgery. Koos grade IV was predictive of radiographic tumor growth after radiosurgery compared to grades I to III (p = 0.02). Treatment failure occurred in 9 of 119 patients (8%); median time to failure was 29 months (range, 4-70 months). The actuarial rates of tumor control at 1, 3, 5, and 7 years were 96%, 94%, 88%, and 88%, respectively. CKRS affords effective tumor control for acoustic neuromas with an acceptable rate of hearing preservation. Further studies are needed to compare CKRS to single-fraction radiosurgery for acoustic neuromas.

Current consensus on optimal treatment of vestibular schwannoma remains poorly established; treatment options include observation, stereotactic radiosurgery, microsurgical resection, medical therapy, or a combination of these. Treatment should be individualized and incorporate the multitude of patient- and tumor-specific characteristics known to affect outcome. Treatment paradigms for sporadic and neurofibromatosis type 2-related tumors are distinct and decision-making in neurofibromatosis type 2 is uniquely challenging. In all cases, treatment should maximize tumor control and minimize functional deficit.

Background and Purpose: Photon Stereotactic Body Radiotherapy (SBRT) for primary and metastatic tumors of the liver is challenging for larger lesions. An in silico comparison of paired SBRT and Stereotactic Body Proton Therapy (SBPT) plans was performed to understand the potential advantages of SBPT as a function of tumor size and location. Methods and materials: Theoretical tumor volumes with maximum diameter of 1–10 cm were contoured in the dome, right inferior, left medial, and central locations. SBRT and SBPT plans were generated to deliver 50 Gy in 5 fractions, max dose

Background and purpose Accelerated repopulation (AR) can compromise tumor control after conventional radiotherapy for fast-growing tumors. Standard AR models assume it begins at a fixed time, with repopulation rates independent of the number of clonogens killed. We investigate the validity and significance of an alternative model where onset-time and rate of AR depend on the number of clonogens killed, and thus on dose and dose-fractionation. Materials and methods We analyzed tumor control (TCP) from randomized trials for head and neck cancer (HNC, 7283 patients), featuring wide ranges of doses, times, and fractionation-schemes. We used the linear-quadratic model with the standard dose-independent AR model, or with an alternative dose-dependent model, where AR onset and rate depend on clonogen killing. Results The alternative dose-dependent model of AR provides significantly-improved descriptions of a wide range of randomized clinical data, relative to the standard dose-independent model. This preferred model predicts that, for currently-used HNC fractionation schemes, the last 5 fractions do not increase TCP, but simply compensate for increased accelerated repopulation. Conclusions The preferred dose-dependent AR model predicts that, for standard fractionation schemes currently used to treat HNC, the final week (5 fractions) could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower overall dose.

The physical characteristics of proton therapy result in steeper dose gradients and superior dose conformality compared to photon therapy. These properties render proton therapy ideal for skull base tumors requiring dose escalation for optimal tumor control, and may also be beneficial for brain tumors as a means of mitigating radiation-related adverse effects. This review summarizes the literature regarding the role of proton therapy compared to photon therapy in the treatment of adult brain and skull base tumors.

Purpose The log file-based method cannot display dosimetric changes due to linac component miscalibration because of the insensitivity of log files to linac component miscalibration. The purpose of this study was to supply dosimetric changes in log file-based patient dose calculations for double-arc volumetric-modulated arc therapy (VMAT) in head-and-neck cases. Methods and materials Fifteen head-and-neck cases participated in this study. For each case, treatment planning system (TPS) doses were produced by double-arc and single-arc VMAT. Miscalibration-simulated log files were generated by inducing a leaf miscalibration of ±0.5 mm into the log files that were acquired during VMAT irradiation. Subsequently, patient doses were estimated using the miscalibration-simulated log files. Results For double-arc VMAT, regarding planning target volume (PTV), the change from TPS dose to miscalibration-simulated log file dose in Dmean was 0.9 Gy and that for tumor control probability was 1.4%. As for organ-at-risks (OARs), the change in Dmean was Conclusions Using the log file-based method for PTV and OARs, the log file-based method estimate of patient dose using the double-arc VMAT has accuracy comparable to that obtained using the single-arc VMAT.

PURPOSE/OBJECTIVE(S) Stereotactic body radiotherapy (SBRT) is standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of maximum standardized uptake value (SUVmax) on FDG-PET/CT before and after SBRT may stratify tumor control and survival outcomes. MATERIALS/METHODS Retrospective chart review identified patients with T1-2N0M0 NSCLC who were only treated with SBRT between 2012 and 2019. Pretreatment SUVmax and percent change in SUVmax at 3 and 6 months following SBRT were assessed as independent predictors of local control (LC), regional failure-free survival (RFFS), distant failure-free survival (DFFS), progression-free survival (PFS), and overall survival (OS). Receiver operator characteristic (ROC) analysis yielded optimal cut points for comparison. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. RESULTS 71 (43.6%) out of 163 patients underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 - 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. For DFFS, pretreatment SUVmax greater than 4 had an aHR of 3.33 (95% CI 1.42 - 7.84, P = 0.006). Pre-SBRT SUVmax over 12.3 had an aHR of 2.80 (95% CI 1.3 - 6.2, P = 0.011) for PFS, and a cut point of 12.6 had an aHR of 3.00 (95% CI 1.6 - 5.8, P = 0.003) for OS. Pretreatment SUVmax did not significantly predict LC or RFFS. At 3 months following SBRT, an SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 - 0.91, P = 0.018). A 6-month SUVmax decrease of more than 53% was associated with better LC (P = 0.038), and a decrease over 11% was associated with improved RFFS (aHR = 0.12, 95% CI 0.02 - 0.96, P = 0.046). Change in SUVmax was not significantly associated with DFFS, PFS, or OS at either time point. No factors other than performance status for PFS and OS were significant. CONCLUSION At 3 and 6 months following SBRT, cut points for percentage change in SUVmax can stratify risk of local recurrence and possibly regional recurrence. Pretreatment SUVmax cutoffs can predict distant failure, progression-free survival, and overall survival in early-stage NSCLC.

Recent findings (Tsabar et al.) demonstrate that human cancer cells that evade the cell cycle blockage normally imposed by DNA damage experience sustained p53 signaling upon MDM2 degradation by caspase 2. Such a response may be connected to the delivery of immunostimulatory signals to ensure the elimination of genetically instable cancer cells.

The combination of radiotherapy modalities with external bundles and systemic radiotherapy (CIERT) could be a reliable alternative for patients with multiple lesions or those where treatment planning maybe difficult because organ(s)-at-risk (OARs) constraints. Radiobiological models should have the capacity for predicting the biological irradiation response considering the differences in the temporal pattern of dose delivering in both modalities. Two CIERT scenarios were studied: sequential combination in which one modality is executed following the other one and concurrent combination when both modalities are running simultaneously. Expressions are provided for calculation of the dose-response magnitudes Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP). General results on radiobiological modeling using the linear-quadratic (LQ) model are also discussed. Inter-subject variation of radiosensitivity and volume irradiation effect in CIERT are studied. OARs should be under control during the planning in concurrent CIERT treatment as the administered activity is increased. The formulation presented here may be used for biological evaluation of prescriptions and biological treatment planning of CIERT schemes in clinical situation.

Summary Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We re-engineered co-detection by indexing (CODEX) for paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers. We identified nine conserved, distinct cellular neighborhoods (CNs)—a collection of components characteristic of the CRC iTME. Enrichment of PD-1+CD4+ T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferior outcomes. This study provides a framework for interrogating how complex biological processes, such as antitumoral immunity, occur through concerted actions of cells and spatial domains., Graphical Abstract, Highlights • FFPE-CODEX multiplexed tissue imaging of 56 markers in 140 tissues of 35 CRC patients • Cellular neighborhoods reveal spatial organization of the tumor microenvironment • Altered organization of tumor and immune components in low- versus high-risk patients • Local enrichment of PD-1+CD4+ T cells correlates with survival in high-risk patients, A multiplexed tissue imaging and computational analysis framework applied to colorectal cancer allows interrogation of how spatial organization of the immune tumor microenvironment is linked to clinical outcomes.

Summary Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control., Graphical abstract, Highlights Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) response Combinations of distantly but not closely related arenavirus vectors eliminate tumors Vector backbone-targeted CTL responses compete against tumor self-reactive CTLs Optimized vector combinations reshuffle immunodominance to break self-tolerance, Therapeutic tumor vaccination should break self-tolerance. Assessing combinations of engineered arenavirus vectors, Bonilla et al. find that distantly related vector combinations reshuffle T cell immunodominance hierarchies to break self-tolerance and eliminate established solid tumors, whereas closely related vectors interfere because of immunodominance of anti-vector CD8 T cells rather than antibodies.

Background Cystic vestibular schwannomas (VS) are associated with unpredictable growth behavior and potentially worse surgical outcomes compared with their solid counterparts. Growth control and potential adverse effects of radiosurgery for cystic VS have created concerns surrounding this modality. We sought to compare the treatment efficacy and safety profile of radiosurgery between cystic and solid VS through a systematic review. Methods PubMed, EMBASE, Web of Science, and Cochrane were searched for related terms and studies reporting radiosurgical outcomes of cystic and solid VS. A meta-analysis was performed to compare the rates of tumor control. Random-effect models with generic inverse variance method was used to calculate overall pooled estimates. Study quality was assessed with the Newcastle Ottawa Criteria. Results In total, 2989 studies were retrieved, and 6 including 1358 VS (79.89% solid; 20.11% cystic, median follow-up range 31.8–150 months) were selected. The median maximal dose was 25 Gy (range, 13–36 Gy) and the median marginal tumor dose was 12 Gy (10–18 Gy). There was no difference between cystic and solid VS (risk ratio, 1.02; 95% confidence interval 0.94–1.10; P = 0.69; I2 = 78%). Transient enlargement of cystic tumors may be associated with trigeminal or facial neuropathy. Conclusions The evidence collected by this study suggests that radiosurgery for cystic VS exhibits effective tumor control probabilities similar to solid VS. Consensus definitions and standard criteria are needed in the future to better understand the patterns of tumor growth and response to treatment following radiosurgery for cystic VS, as well as long-term neurological and functional outcomes.

Because evaluation of Gamma Knife radiosurgery (GKRS) for brain metastases (METs) has mainly been based on overall or progression-free survival rates, that is, patients' general condition and control of the primary disease, we focused on factors influencing local tumor control after GKRS for METs from breast cancer. Data were retrospectively collected from our institution's records of patients who had undergone GKRS twice or more for METs from breast cancer. Failed GKRS was defined as a tumor needing re-treatment by further GKRS or having already been treated by other modalities prior to later GKRS procedures. Influences of various factors on local tumor control were examined. GKRS was performed on 623 tumors in 123 sessions in 90 patients. Median follow up was 9months (range 1-41months). According to multivariate analysis, use of HER2-targeting agents, (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.18-0.99, p=0.049), five or more lesions (HR 0.24, 95% CI 0.11-0.51, p 1.2cm3 (HR 3.12, 95% CI 1.62-6.02, p

To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS).Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors,8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resection received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients.Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group.Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.

Background Chondroblastoma is an uncommon benign bone tumor with an incidence of 1 to 2% among all primary bone tumors. In the past, treatment for chondroblastoma has been highly variable leading to different rates of recurrences. Therefore we aimed to determine: (1) the rate of recurrence, (2) the complication rate, (3) and functional outcome after intralesional curettage of chondroblastoma. Hypotheses Intralesional curettage with high speed burring and packing can avoid local recurrences. Patients and methods Experiences of 22 patients with chondroblastoma of the bone were retrospectively reviewed. The patient group consisted of 16 men; 6 women; mean age 24 years (range; 12–58 years) affecting in 15 the lower- (68%) and in seven the upper extremity (32%). Results There was no local recurrence or malignant transformation. All patients underwent intralesional curettage, followed by defect filling presenting in 19 patients (87%) excellent clinical and oncological results (mean MSTS 98.9). Complications were seen in two patients. Pain was the main revealing symptom of the chondroblastoma (n = 16, 73%). Mean follow-up of all patients was 114 months (range, 25 to 480 months). Discussion Aggressive curettage and packing provided excellent local tumor control and functional results in our patients with chondroblastoma. Malignant transformation is extremely rare, however, present in literature but was not seen in any of our patients. Level of evidence Level IV, retrospective study.

The impact of a rectal spacer and an increased near maximum target dose in VMAT prostate SBRT is studied. For a group of 11 patients (35Gy-in-five-fractions VMAT prostate SBRT) a set of 4 plans were generated, namely two VMAT plans, with D2%⩽37.5Gy (Hom) and with D2%⩽40.2Gy (Het), were created for each of two CT scans taken before (NoSpc) and after (Spc) transperineal spacer insertion. Consequently the methodology for parameter invariant TCP (tumor control probability) plan ranking was applied for comparison of the plans in terms of tumor control. NTCPs (normal tissue complication probabilities) were calculated for rectum and bladder using Lyman's model. For all 11 patients the TCP plan ranking has shown that the Het plans would perform considerably better in TCP terms than the Hom ones. The plans without rectal spacer were ranked worse compared to those with rectal spacer except for one set of Hom plans. The calculated NTCPs for rectum produced by the Het plans were quite similar to the NTCPs of the Hom ones. The rectal NTCPs of the Hom Spc plans were always lower than the NTCPs of the Hom NoSpc plans. The NTCP values for bladder were extremely low in all cases. The use of rectal spacer leads in general to lower risk of rectal complications, as expected, and even to better tumor control. Plans with increased near maximum target dose (D2%⩽40.2Gy) are expected to perform much better in terms of tumor control than those with D2%⩽37.5Gy.

Radio-enhancers, metal-based nanosized agents, could play a key role in oncology. They may unlock the potential of radiotherapy by enhancing the radiation dose deposit within tumors when the ionizing radiation source is 'on', while exhibiting chemically inert behavior in cellular and subcellular systems when the radiation beam is 'off'. Important decision points support the development of these new type of therapeutic agents originated from nanotechnology. Here, we discuss from an industry perspective, the interest of developing radio-enhancer agents to improve tumor control, the relevance of nanotechnology to achieve adequate therapeutic attributes, and present some considerations for their development in oncology.

Customized intraoral devices help the radiation oncologist minimize the adverse effects of radiation and maximize the tumor control rate by keeping the anatomic structures in a consistent position during each fraction of radiation treatment. This article illustrates the fabrication of a bolus-type positioning device for a combined intraoral/extraoral defect treated with proton radiation therapy.

Treatment planning for patients with synchronous bilateral breast cancer (SBBC) is challenging due to the technical complexity of bilateral treatment. To minimize both high-dose and low-dose volumes of the heart and lungs being irradiated, we proposed an efficient and simple strategy for volumetric modulated arc therapy (VMAT) treatment planning in this study. Five SBBC patients were enrolled in this study. We utilized two pseudo block planning structures to minimize the high-dose volume of the whole lungs and heart and confine the low-dose areas in normal organs for VMAT planning. The prescription delivered was 45 Gy in 25 fractions to the whole breast. The VMAT treatment plan consisted of two partial arcs. In terms of the whole lungs, the average V5Gy, V10Gy and V20Gy in the VMAT-B plan (with two pseudo planning block structures) for the five patients were 34.8 ± 7.2%, 23.4 ± 5.0% and 14.8 ± 3.0%, respectively. For the VMAT-NB plan (without two pseudo planning block structures), the average V5Gy, V10Gy and V20Gy were 38.6 ± 6.8%, 27 ± 5.9% and 18.4 ± 4.0%, respectively. For the heart, the average V5Gy, V10Gy, V20Gy and V30Gy in the VMAT-B plan were 19.6 ± 3.1%, 7.0 ± 2.5%, 2.2 ± 1.2% and 0.7 ± 0.7%, respectively, while the mean values in the VMAT-NB plan were 26.2 ± 6.3%, 11.3 ± 3.9%, 3.9 ± 1.8% and 1.5 ± 1.1%, respectively. We designed an approach to reduce both the high-dose and low-dose volumes by utilizing pseudo planning structures in the VMAT treatment plan. The dosimetric results of this study showed that the pseudo block structures have the potential to reduce the risks of radiation pneumonitis and heart disease, while preserving the same tumor control rate.

Objective The use of SRS for treatment of cystic vestibular schwannoma is a topic of mild controversy. This review serves to introduce a renewed understanding of the efficacy of SRS as a viable treatment modality for cystic VS. Patients and methods This study was conducted in accordance with the PRISMA guidelines. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, Web of Science, and Cochrane databases. Meta-analysis was conducted on tumor control rates and heterogeneity between articles was assessed using τ2, Cochran’s Q, and I2 statistics. Results A total of 246 patients underwent SRS for cystic VS, with reported mean or median follow-up ranging from 49.7 to 150 months, and an overall range of 6–201 months. Following SRS treatment for cystic VS across all studies, 92% of patients had tumor control at follow up, (95%-CI: 88–95%). Tumor control rate specifically for patients who underwent GammaKnife was 93% (95-CI: 88%–95%). Conclusion Despite the paucity of pertinent data, the results of our meta-analysis suggest that SRS exhibits effective tumor control rates in patients with cystic VS. Therefore, SRS can be considered a viable treatment modality when choosing amongst interventions for cystic VS.