Probability Of Local Control Research Articles

Pituitary neuroendocrine tumors treated with stereotactic radiosurgery.

Pituitary neuroendocrine tumors (pitNETs) are benign tumors that may recur after surgical resection or persist following medical management. The objective of this study was to evaluate outcomes and toxicities of patients with pitNETs treated with stereotactic radiosurgery (SRS) at a single institution. We completed a retrospective, single-institution study of patients with pitNETs treated with frame-based, single-fraction, cobalt-60 SRS between September 2005 and June 2023. The primary endpoint was local tumor control. Secondary endpoints included endocrine control (for functional tumors), overall survival, and toxicities. A total of 88 lesions in 83 patients were treated with SRS. Most lesions (70%) were non-functional tumors. Of the 26 functioning tumors, 6 patients achieved endocrine remission with SRS alone (23%), and the remainder achieved remission with combined medical management. With a median patient follow-up of 4.7 years, no local tumor recurrences were observed with an estimated local control probability of 100%. Two- and five-year overall survival estimates were 97% (95% confidence interval [CI] 89-99) and 95% (95% CI 84-98), respectively. Causes of death were unrelated to PitNET or SRS. Twelve patients (14%) developed hypopituitarism after SRS. Despite the 34 lesions that were ≤ 3mm from optic structures, no patients developed any optic neuropathy or visual decline post SRS. SRS is a highly effective modality for recurrent or residual pitNETs. This study observed a local control of 100% with no cases of optic toxicities after a median follow-up of 4.7 years. These observed findings suggest that dose de-escalation may be possible for future treatment of pitNETs.

Stereotactic Body Radiotherapy for Renal Cell Carcinoma-A Review of Use in the Primary, Cytoreductive and Oligometastatic Settings.

Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published.

Histology-driven hypofractionated radiation therapy schemes for early-stage lung adenocarcinoma and squamous cell carcinoma

Background and PurposeHistology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Material and MethodsThe least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. ResultsA fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1–30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively. ConclusionWe presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.

Deep Learning-Guided Dosimetry for Mitigating Local Failure of Patients With Non-Small Cell Lung Cancer Receiving Stereotactic Body Radiation Therapy

Purpose: NSCLC SBRT with 50 Gy/5 fractions is sometimes considered controversial, as the nominal BED of 100 Gy is felt by some to be insufficient for long-term local control of some lesions. In this study, we analyzed such patients using explainable deep learning techniques, and consequently proposed appropriate treatment planning criteria. These novel criteria could help planners achieve optimized treatment plans, for maximal local control. Methods and MaterialsA total of 535 Patients treated with 50 Gy/ 5 fractions were used to develop a novel deep learning local response model. A multi-modality approach, incorporating CT images, 3D dose distribution and patient demographics, combined with a discrete-time survival model was applied to predict time to failure and the probability of local control. Subsequently, an integrated Grad-CAM method was used to identify the most significant dose-volume metrics predictive of local failure and their optimal cut-points. ResultsThe model was cross-validated showing an acceptable performance (c-index: 0.72, 95% CI: 0.68-0.75); the testing c-index was 0.69. The model's spatial attention was concentrated mostly in the tumors’ periphery (PTV-IGTV) region. Statistically significant dose-volume metrics in improved local control were BED Dnear-min≥103.8 Gy in IGTV (HR, 0.31; 95% CI, 015-0.63), V104≥98% in IGTV (HR, 0.30; 95% CI, 0.15-0.60), gEUD≥103.8 Gy in PTV-IGTV (HR, 0.25; 95% CI, 0.12-0.50) and Dmean≥104.5 Gy in PTV-IGTV (HR, 0.25; 95% CI, 0.12-0.51). ConclusionsDeep learning identified dose-volume metrics have shown significant prognostic power (Logrank, p=0.003) and could be used as additional actionable criteria for treatment planning in NSCLC SBRT patients receiving 50 Gy in 5 fractions. While our data do not confirm or refute that a significantly higher BED for the prescription dose is necessary for tumor control in NSCLC, it might be clinically effective to escalate the nominal prescribed dose from BED 100 Gy to 105 Gy.

Dose-effect relationship of linear accelerator based stereotactic radiotherapy for brain metastases

ObjectiveThe purpose of this study is to reveal the dose-effect relationship of linear accelerator (LINAC)-based stereotactic radiotherapy (SRT) in patients with brain metastases (BM).Materials and methodsThe PubMed, Cochrane, and Web of Science databases were used to identify studies that reported local tumour control after LINAC-based SRT in patients with BMs. Studies of other approaches that could affect local tumour control, such as whole brain radiotherapy, targeted therapy, and immunotherapy, were excluded from the dose-effect relationship analysis. Data extracted included patient and treatment characteristics and tumour local control. Probit model in XLSTAT 2016 was used for regression analysis, and P < 0.05 was set as the statistically significant level.ResultsAfter literature screening, 19 eligible studies involving 1523 patients were included in the probit model regression analysis. There was no significant dose-effect relationship between nominal BED10 and peripheral BED10 versus 12-month local control probability. There were significant dose effect relationships between the centre BED10 and the average BED10 versus the 12-month local control probability, with P values of 0.015 and 0.011, respectively. According to the model, the central BED10 and the average BED10 corresponding to probabilities of 90% 12-month local control were 109.2 GyBED10 (95% confidence interval (CI): 88.7–245.9 GyBED10) and 87.8 GyBED10 (95% CI: 74.3–161.5 GyBED10), respectively. A 12-month local control rate of 86.9% (95% CI: 81.7–89.7%) and 85.5% (95% CI: 81.2–89.2%) can be expected at a centre BED10 of 80 Gy and an average BED10 of 60 Gy, respectively.ConclusionFor patients with BM treated with LINAC-based SRT, more attention should be given to the central and average doses of PTV. A clear definition of the dose prescription should be established to ensure the effectiveness and comparability of treatment.

Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

Effects of Interfraction Dose Variations of Target and Organs at Risk on Clinical Outcomes in High Dose Rate Brachytherapy for Cervical Cancer.

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose and probability of risk-free local control (RFLC) were calculated using the utility model. The IDVs were well-fitted by the left-skewed Beta distribution, which caused a 3.99% decrease in local control probability and a 1.80% increase in treatment failure. Utility with respect to IDV uncertainty increased the RFLC probability by 6.70% and predicted an optimal dose range of 83 Gy-91 Gy EQD2. It was also found that a 10 Gy dose escalation would not affect toxicity. In conclusion, HRCTV IDV uncertainty reduced LC probabilities and increased treatment failure rates. A dose escalation may help mitigate such effects.

Influence of Dose Distribution in the Target on the Values of Integral Radiobiological Criteria Based on Synthetic Dose-Volume Histograms

Purpose: To investigate the influence of absorbed dose distribution in the tumor volume on the values of&#x0D; integral radiobiological criteria, such as the probability of local tumor control (Tumor Control Probability, TCP) and normal tissue complication probability (NTCP), based on synthetic dose-volume histograms (DVH), which enables to assess the treatment effectiveness and probability of complications&#x0D; from healthy organs and tissues.&#x0D; Material and methods: Synthetic dose-volume histograms were considered theoretically possible to analyze the dependence of equivalent uniform dose (EUD) on values of Nimirko model parameters and absorbed dose distribution for both tumor and critical organs. The calculation was carried out in Wolfram&#x0D; Mathematica program based on the algorithm, where an array of absorbed dose values per fraction of&#x0D; irradiation volume with step by absorbed dose was calculated for the given values of absorbed dose and&#x0D; the parameter determining the width of distribution. The resulting array was differentiated to obtain&#x0D; the differential DVH. The EUD values were obtained from the normalized differential DVHs.&#x0D; Results: During analysis of EUD value dependence on parameter a values determining degree of nonlinearity of absorbed dose summation in sub-volumes of irradiation and on absorbed dose distribution&#x0D; the following was revealed: for critical organs at high values of parameter a the essential role belongs to&#x0D; high and average values of absorbed dose, and for tumors at low values of parameter a the main role belongs to the minimum value of absorbed dose. Thus, the value of parameter a should be negative for a&#x0D; tumor, and positive for critical organs, and should be specifically defined for specific structures.&#x0D; Conclusion: To improve the predictive value (prediction) of the effect of radiotherapy using the&#x0D; TCP/NTCP Nimirko model, an adequate definition of the parameter a, the value of which can only be determined from absorbed dose distributions over the volume of anatomical structures within clinical trials, is necessary.

The Microvascular Network Density and Morphology Affect the Radiotherapy Outcome at the Microscale Level: A Computational Analysis.

Half of the cancer patients are treated with radiotherapy to obtain tumor control while minimizing radiation toxicity. In this context, hypoxia is known to determine treatment resistance, driving tumor relapse after treatment. Therefore, we investigated the role of microvasculature density and morphology in shaping the tissue oxygen distribution and consequently affecting the treatment outcome. We developed an advanced computational model to describe oxygen delivery in the vascular network and the surrounding tissue. A peculiar aspect of the model is its mesoscale mixed-dimensional approach, which allows the explicit inclusion of vascular network geometry and the description of the red blood cells' effect. The oxygen delivery is modeled considering both diffusive and convective phenomena. A 30 × 2GyRBE treatment is delivered in silico simulating photons, protons, and carbon ions. First, we estimated the surviving fraction by the classical linear quadratic model modified to account for the oxygen effect. Then, leveraging the 3D description of the surviving fraction at the microenvironment scale, we compute the local tumor control probability (LTCP) in different oxygenation states (reference, acute hypoxia, high oxygen consumption). We report correlations between the LTCP and the hypoxic volume fractions (with pO2 lower than 1 mmHg) starting with photons. These hypoxic regions are present locally, even in highly vascularized tissue, if the network is not uniformly distributed, as it might be in cancer. They are also present in tissue with low microvascular density, even with regular morphology. Interestingly, the domain considered is comparable to or smaller than the clinical imaging standard voxel dimension, and the average oxygen partial pressure in the tissue region fails to spot treatments with low LTCP, questioning whether these hypoxia areas are visible clinically via imaging. Protons have a similar effect, highlighting a similar behavior across the oxygenation levels at the microscale level. Finally, carbon ions seem more effective than photons and protons in the presence of hypoxia due to the lower oxygen effect at high LET. For this reason, the treatment with carbon ions results in high LTCPs, whatever vascular network is considered (density and morphology differences). These results show the effect of microvascular density and regularity on the radiotherapy outcome and they help us understand how the microvascular network morphology affects tumor oxygenation and the radiotherapy outcome.

Novel Dose Criteria for Lung Cancer SBRT to Improve Local Control in Patients Treated to 50 Gy/5 Fractions Using Deep Learning Methods and Explainability Techniques

To some radiation oncologists, 50 Gy/5 fractions has been considered controversial, as they feel the nominal BED of 100 Gy might be too low for long-term local control of some lesions. We analyzed a large cohort of these patients using a deep learning model to predict local recurrence (LR) and used explainability techniques to extract new dose features important to the model's prediction. Subsequently, we determined optimal cut-points for the most significant metrics to provide actionable criteria for treatment planning in these patients. A total of 535 SBRT lung cancer patients treated between 2009 and 2017 were retrospectively analyzed using a deep learning approach. All patients had NSCLC and all of them were treated with 50 Gy in 5 fractions (100 Gy BED, α/β = 10). Mean clinical maximum tumor diameter was 2.2 cm. There were 31 LR in the dataset with mean follow-up time of 28 months. Mean age was 75 years. CT images, 3D dose distribution and patient demographic details were used to train a deep learning survival model to predict time to failure and probability of local control. Validation, training, and testing were in accordance with TRIPOD criteria. 80 % of the data were used for 5-fold cross-validation (10 iterations) and 20 % was held for independent testing. The Grad-CAM method was applied to identify regions of the dose distribution that are the most significant to the model's decision-making. Based on the results, appropriate dose metrics were proposed, and optimal cut-points were determined to distinguish between lower and higher LR-risk patients. The model has an acceptable performance (c-index: 0.72, 95% CI: 0.68-0.75); the testing c-index was 0.69. Grad-CAM showed that the model's spatial attention was mostly concentrated in the tumor's "PTV-GTV" region. Statistically significant criteria are in Table 1. A novel deep learning model for prediction of LR, incorporating 3D dose data, CT images and patient demographics, was developed and tested. Grad-CAM demonstrated superior significance of peripheral (PTV-GTV) dose features. Subsequently determined optimal cut-points have significant prognostic power (log rank, p<0.001) and could be used as additional criteria in treatment planning. While these data have repercussions in treatment planning, they do not suggest that a significantly higher BED for the prescription dose is necessary for tumor control in NSCLC. Nevertheless, it might be effective to slightly elevate the prescribed dose, i.e., from 100 Gy BED to 104 Gy BED.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

P18.09.A PROTON THERAPY FOR PATIENTS WITH MENINGIOMA - WHAT ABOUT FINANCIAL TOXICITY AND OCCUPATIONAL STATUS?

Abstract BACKGROUND Patients (pts) with meningioma are commonly treated with proton therapy (PT) in order to minimize integral dose to normal brain parenchyma. Considering the high local control probability, preservation of Quality of Life (QoL) is gaining increasing importance.Potential loss of employment, inability to work or need to reduce working hours may lead to financial worries negatively affecting QoL. We investigated the subjective QoL and disease burden in pts with meningioma treated with PT with regards to income, financial toxicity, inability to resume work before and after PT. MATERIAL AND METHODS Data from prospectively assessed questionnaires (EORTC QLQ-C30) including an item for subjective financial difficulties, scaled from 1-4 (1=“not at all” to 4=”very much”), was collected from pts treated with PT for meningioma. Observed time points were prior to start of treatment (t1) and incrementally thereafter (completion of treatment, at 3months (ms),6ms,12ms,24ms,36ms and 48ms;t2-t8). Employment status was collected and net household income was assessed and ranked into 5 groups ranging from &amp;lt;1300€ to &amp;gt;5000€. RESULTS: RESULTS 171pts (39m/131f) aged 20-88yrs (mean 55.1) with meningioma were included. At a mean observation time of 29.6ms, 991 data sets were collected. 37pts (35.9%) reported health-related inability to work before PT. Over follow up (FU), it decreased to 33.8% at 12ms, 27.3% at 24ms, 15.4% at 36ms, 13.6% at 48ms. 34pts (33%) were employed prior to their diagnosis (14part-time, 18full-time). While rates of full-time employment initially decreased, it steadily increased from 1yr FU (t3-t8: 28.7%-59.1%), rates of part-time remained stable (t3-t8:27.2%-27.3%), see figure 1. Subjective financial burden correlated significantly with occupational situation (Spearman;p&amp;lt;0.001) indicating a reduction in patient-reported financial difficulties after commencement of work / increase in working hours. There were no relevant changes in pts´ income (Friedman:p=0.610); however, pts with lower income prior to PT reported subsequently higher levels of financial difficulties (Spearman:p&amp;lt;0.001). Before PT, 69 pts (40%) reported various levels of financial difficulties. Although rates decreased initially at the end of PT (30.2%), they consistently decreased at all subsequent FUs. This reflects the lower burden of financial toxicity over time. CONCLUSION At a mean observation time of &amp;gt;2 years, this study prospectively analyzed the potential impact of proton therapy in patients treated for meningioma. Patients reported an overall increase in employment rate, significant improvement in their financial situation and preservation and gain in their quality of life over time.

CyberKnife® stereotactic radiation therapy for stage I lung cancer and pulmonary oligometastases: is fiducial implantation still relevant?-a cohort study.

Few studies have investigated whether there is a difference in local control or overall survival rates following treatment with robotic stereotactic body radiation therapy (SBRT) with or without prior fiducial marker implantation. Our study aimed to investigate this in patients with primary or secondary lung tumors. A retrospective study was conducted at the Institut de Cancérologie de Lorraine of patients treated for primary lung cancer or pulmonary oligometastases with SBRT from January 2013 to July 2016. We included patients at least 18 years old who had stage I non-small cell lung cancer (NSCLC) or lung metastases and a follow-up of at least 1 month. A total of 294 patients were included. Tumors included 122 lung metastases, 89 stage I NSCLC, and 83 non-histologically confirmed lung lesions. The tracking methods were Synchrony® in 191 cases (119 gold seeds and 72 coils) and Xsight® Spine with 4D computed tomography in 103 cases. Median follow-up was 31.6 months [interquartile range (IQR), 18.1-50.2 months]. The two- and five-year probability of local control were respectively 92.22% [95% confidence interval (CI): 0.89-0.95] and 85.35% (95% CI: 0.79-0.99). The two- and five-year probability of overall survival were respectively 87.46% and 72.77% (P=0.586). Local control rates did not significantly differ between techniques at 2 and 5 years (P=0.685) (gold seeds, coils or Xsight® Spine) within tumors grouped by location, gross tumor volume (GTV) (respectively P=0.9, P=0.7, and P=0.4), planning target volume (PTV) (respectively P=0.4, P=0.9, and P=0.7), or PTV/GTV ratio (respectively P=0.6, P=0.6, and P=0.5). Metastasis-free survival and Overall survival rates did not significantly differ between techniques at 2 and 5 years (P=0.664 and P=0.586, respectively). There were no grade 4 or 5 toxicities and only one grade 3 pneumonitis and one grade 3 pneumothorax. Fiducial-less SBRT using Xsight® Spine is a safe alternative to Synchrony® using gold seeds or coils, with comparable local control and overall survival rates and a similar toxicity profile.

Overcoming radioresistance with the hypoxia-activated prodrug CP-506: A pre-clinical study of local tumour control probability

Background and purposeTumour hypoxia is an established radioresistance factor. A novel hypoxia-activated prodrug CP-506 has been proven to selectively target hypoxic tumour cells and to cause anti-tumour activity. The current study investigates whether CP-506 improves outcome of radiotherapy in vivo. Materials and methodsMice bearing FaDu and UT-SCC-5 xenografts were randomized to receive 5 daily injections of CP-506/vehicle followed by single dose (SD) irradiation. In addition, CP-506 was combined once per week with fractionated irradiation (30 fractions/6 weeks). Animals were followed-up to score all recurrences. In parallel, tumours were harvested to evaluate pimonidazole hypoxia, DNA damage (γH2AX), expression of oxidoreductases. ResultsCP-506 treatment significantly increased local control rate after SD in FaDu, 62% vs. 27% (p = 0.024). In UT-SCC-5, this effect was not curative and only marginally significant. CP-506 induced significant DNA damage in FaDu (p = 0.009) but not in UT- SCC-5. Hypoxic volume (HV) was significantly smaller (p = 0.038) after pretreatment with CP-506 as compared to vehicle in FaDu but not in less responsive UT-SCC-5. Adding CP-506 to fractionated radiotherapy in FaDu did not result in significant benefit. ConclusionThe results support the use of CP-506 in combination with radiation in particular using hypofractionation schedules in hypoxic tumours. The magnitude of effect depends on the tumour model, therefore it is expected that applying appropriate patient stratification strategy will further enhance the benefit of CP-506 treatment for cancer patients. A phase I-IIA clinical trial of CP-506 in monotherapy or in combination with carboplatin or a checkpoint inhibitor has been approved (NCT04954599).

Metabolic factors associated with the prognosis of oligometastatic patients treated with stereotactic body radiotherapy.

Over the past two decades, it has been established that cancer patients with oligometastases, i.e., only a few detectable metastases confined to one or a few organs, may benefit from an aggressive local treatment approach such as the application of high-precision stereotacticbody radiotherapy (SBRT). Specifically, some studies have indicated that achieving long-term local tumor control of oligometastases is associated with prolonged overall survival. This motivates investigations into which factors may modify the dose-response relationship of SBRT by making metastases more or less radioresistant. One such factor relates to the uptake of the positron emission tomography tracer 2-deoxy-2-[18F]fluoro-D-glucose (FDG) which reflects the extent of tumor cell glycolysis or the Warburg effect, respectively. Here we review the biological mechanisms how the Warburg effect drives tumor cell radioresistance and metastasis and draw connections to clinical studies reporting associations between high FDG uptake and worse clinical outcomes after SBRT for oligometastases. We further review the evidence for distinct metabolic phenotypes of metastases preferentially seeding to specific organs and their possible translation into distinct radioresistance. Finally, evidence that obesity and hyperglycemia also affect outcomes after SBRT will be presented. While delivered dose is the main determinant of a high local tumor control probability, there might be clinical scenarios when metabolic targeting could make the difference between achieving local control or not, for example when doses have to be compromised in order to spare neighboring high-risk organs, or when tumors are expected to be highly therapy-resistant due to heavy pretreatment such as chemotherapy and/or radiotherapy.

Abstract CT151: A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma

Abstract Introduction: Stereotactic body radiation therapy (SBRT) for the treatment of hepatocellular carcinoma (HCC) remains a challenge due to high rates of toxicity in patients with impaired liver function or tumors not amenable to thermal ablation. We performed a single-arm prospective phase II clinical trial utilizing a novel treatment paradigm optimizing the utility of SBRT based on the individual patient’s probability for tumor control traded off against the risk of liver injury. We hypothesized that maximizing the utility of treatment would decrease toxicity while achieving the same tumor control rate as standard therapy. Methods: Patients with Child-Pugh (CP) A to B7 disease with tumors &amp;gt;3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an IRB approved clinical trial to undergo SBRT with baseline dose optimization and mid-treatment response adaptation. Optimization and adaptation were based on the expected utility of treatment, calculated as a weighted average of the probability of 4 combinations of toxicity and efficacy outcomes. These calculations were based on the individual patient’s baseline indocyanine green retention at 15 minutes or albumin-bilirubin score (ALBI), CP score, intended dose and fractionation, and mean liver dose with the goal of maximizing the difference between the probability of local control compared to the probability of treatment-related toxicity. Primary endpoints were rate of liver decompensation as measured by ≥2 point change in CP score within 6 months, and lesion-specific local control. Overlap weighting was used to compare patients treated on protocol with patients receiving conventional SBRT at another high-volume cancer center. Results: 56 patients with 80 tumors met inclusion criteria and had a median follow-up of 11.2 months. 44 tumors with a median size of 3.8 cm were treated in CP-A to B7 patients, while 36 tumors with a median size of 2.1 cm were treated in CP ≥ B8 patients. Optimization resulted modification of initial dose for 38% of patients. Sixty-eight percent of patients underwent mid-treatment adaptation with either omission or dose reduction of the final two treatments based on change in expected utility. The 1 year freedom from local progression was 94%. A total of 21% of patients experienced a ≥ 2 point change in CP score within 6 months. Overlap weighted analysis revealed similar local control (HR 0.69, 95% CI [0.25-1.91], p = 0.48), and overall survival (HR 1.45, 95% CI [0.69-3.0], p = 0.33), with decreased toxicity (OR 0.26, 95% CI [0.07 - 0.99], p = 0.048) compared to conventional SBRT. Conclusion: SBRT for HCC patients with large tumors or poor liver function can be optimized via an individualized, utility-based treatment paradigm which may decrease treatment-related toxicity while maintaining tumor control. Citation Format: Daniel J. Herr, Chang Wang, Mishal Mendiratta-Lala, Martha Matuszak, Charles S. Mayo, Yue Cao, Neehar Parikh, Randy Ten Hanken, Dawn Owen, Teodor Stanescu, Michael Yan, Laura A. Dawson, Matthew Schipper, Theodore S. Lawrence, Kyle C. Cuneo. A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT151.

A clinical decision support system for AI-assisted decision-making in response-adaptive radiotherapy (ARCliDS)

Involvement of many variables, uncertainty in treatment response, and inter-patient heterogeneity challenge objective decision-making in dynamic treatment regime (DTR) in oncology. Advanced machine learning analytics in conjunction with information-rich dense multi-omics data have the ability to overcome such challenges. We have developed a comprehensive artificial intelligence (AI)-based optimal decision-making framework for assisting oncologists in DTR. In this work, we demonstrate the proposed framework to Knowledge Based Response-Adaptive Radiotherapy (KBR-ART) applications by developing an interactive software tool entitled Adaptive Radiotherapy Clinical Decision Support (ARCliDS). ARCliDS is composed of two main components: Artifcial RT Environment (ARTE) and Optimal Decision Maker (ODM). ARTE is designed as a Markov decision process and modeled via supervised learning. Given a patient’s pre- and during-treatment information, ARTE can estimate treatment outcomes for a selected daily dosage value (radiation fraction size). ODM is formulated using reinforcement learning and is trained on ARTE. ODM can recommend optimal daily dosage adjustments to maximize the tumor local control probability and minimize the side effects. Graph Neural Networks (GNN) are applied to exploit the inter-feature relationships for improved modeling performance and a novel double GNN architecture is designed to avoid nonphysical treatment response. Datasets of size 117 and 292 were available from two clinical trials on adaptive RT in non-small cell lung cancer (NSCLC) patients and adaptive stereotactic body RT (SBRT) in hepatocellular carcinoma (HCC) patients, respectively. For training and validation, dense data with 297 features were available for 67 NSCLC patients and 110 features for 71 HCC patients. To increase the sample size for ODM training, we applied Generative Adversarial Networks to generate 10,000 synthetic patients. The ODM was trained on the synthetic patients and validated on the original dataset. We found that, Double GNN architecture was able to correct the nonphysical dose-response trend and improve ARCliDS recommendation. The average root mean squared difference (RMSD) between ARCliDS recommendation and reported clinical decisions using double GNNs were 0.61 [0.03] Gy/frac (mean [sem]) for adaptive RT in NSCLC patients and 2.96 [0.42] Gy/frac for adaptive SBRT HCC compared to the single GNN’s RMSDs of 0.97 [0.12] Gy/frac and 4.75 [0.16] Gy/frac, respectively. Overall, For NSCLC and HCC, ARCliDS with double GNNs was able to reproduce 36% and 50% of the good clinical decisions (local control and no side effects) and improve 74% and 30% of the bad clinical decisions, respectively. In conclusion, ARCliDS is the first web-based software dedicated to assist KBR-ART with multi-omics data. ARCliDS can learn from the reported clinical decisions and facilitate AI-assisted clinical decision-making for improving the outcomes in DTR.

Magnetic resonance imaging signal characteristics associated with prognosis of skull base chordoma after gamma knife radiosurgery

To investigate the association between the magnetic resonance imaging (MRI) signal characteristics of skull base chordoma and radiosurgical outcomes. Twenty-four patients with skull base chordomas treated with Gamma Knife radiosurgery (GKRS) after previous surgical resection were retrospectively (2001-2021) examined. Pre-GKRS MRIs were analyzed for RT2 (tumor-to-brainstem signal intensity ratio on T2-weighted imaging), RCE (tumor-to-brainstem signal intensity ratio on contrast-enhanced T1-weighted imaging), and mean apparent diffusion coefficient (ADC). Correlations of the parameters with patient survival and local tumor progression were made by using Cox regression and Kaplan-Meier analyses. During a median follow-up of 46months after GKRS, 9 patients died with significantly more local tumor progression events (median number: 2 vs 0, P = .012) than did 15 alive patients. On multivariable analysis, higher mean ADC was associated with longer patient survival (P = .016) after GKRS. The actuarial 5-year overall survival rates were 88.9% versus 54.7% for chordomas with an ADC of ≥ 1270 × 10-6 mm2/s versus < 1270 × 10-6 mm2/s. RT2 < 1.5 (P = .038) and RCE > 1.57 (P = .022) were associated with a lower probability of local tumor control. Lower mean ADC values are associated with shorter patient survival in skull base chordomas after GKRS. Diffusion-weighted imaging may help in GKRS planning and outcome prediction for these patients.

Dose–effect relationship of stereotactic body radiotherapy in non-small cell lung cancer patients

ObjectiveTo establish the dose effect relationship between the dose parameters of stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) and the local tumor control rate.Materials and methodsA comprehensive literature search was conducted using PubMed, the Web of Science and the Cochrane databases to determine the articles treated with SBRT in early-stage NSCLC. Original studies with complete prescription dose information, tumor local control rate and other important parameters were screened and reported. Probit model in XLSTAT 2016 was used for regression analysis, and P < 0.05 was set as a statistically significant level.ResultsAfter literature screening, 22 eligible studies were included in probit model regression analysis, involving 1861 patients. There is no significant dose effect relationship between nominal BED10 and peripheral BED10 versus 3 years local control probability. There were significant dose effect relationships between the center BED10 and the average BED10 versus the 3 years local control probability, with P values are 0.001 and < 0.0001, respectively. According to the results of this model, the 3 years local control rate of 90.5% (87.5–92.1%) and 89.5% (86.7–91.0%) can be expected at the center BED10 of 180 Gy or the average BED10 of 140 Gy, prospectively.ConclusionsFor NSCLC treated with SBRT, more attention should be paid to the central dose and average dose of PTV. A set of clear definition in the dose prescription should be established to ensure the effectiveness and comparability of treatment.

High-Dose-Rate Brachytherapy as an Organ-Sparing Treatment for Early Penile Cancer.

Low-dose-rate brachytherapy is an effective organ-sparing treatment for patients with early-stage penile cancer. However, only limited data are available on the role of high-dose-rate brachytherapy (HDR-BT) in this clinical setting. Between 2002 and 2020, 31 patients with early penile cancer were treated at our center with interstitial HDR BT at a dose of 18 × 3 Gy twice daily. A breast brachytherapy template was used for the fixation of stainless hollow needles. The median follow-up was 117.5 months (range, 5-210). Eight patients (25.8%) developed a recurrence; of these, seven were salvaged by partial amputation. Six patients died of internal comorbidities or a second cancer. The probability of local control at 5 and 10 years was 80.7% (95% CI: 63.7-97.7%) and 68.3% (95% CI: 44.0-92.6%), respectively. Cause-specific survival was 100%. Only one case of radiation-induced necrosis was observed. The probability of penile sparing at 5 and 10 years was 80.6% (95% CI: 63.45-97.7%) and 62.1% (95% CI: 34.8-89.4%), respectively. These results show that HDR-BT for penile cancer can achieve results comparable to LDR-BT with organ sparing. Despite the relatively large patient cohort-the second largest reported to date in this clinical setting-prospective data from larger samples are needed to confirm the role of HDR-BT in penile cancer.