Local Tumor Control Probability Research Articles

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.

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.

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.

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.

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.

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.

An investigation of the conformity, feasibility, and expected clinical benefits of multiparametric MRI-guided dose painting radiotherapy in glioblastoma.

BackgroundNew technologies developed to improve survival outcomes for glioblastoma (GBM) continue to have limited success. Recently, image-guided dose painting (DP) radiotherapy has emerged as a promising strategy to increase local control rates. In this study, we evaluate the practical application of a multiparametric MRI model of glioma infiltration for DP radiotherapy in GBM by measuring its conformity, feasibility, and expected clinical benefits against standard of care treatment.MethodsMaps of tumor probability were generated from perfusion/diffusion MRI data from 17 GBM patients via a previously developed model of GBM infiltration. Prescriptions for DP were linearly derived from tumor probability maps and used to develop dose optimized treatment plans. Conformity of DP plans to dose prescriptions was measured via a quality factor. Feasibility of DP plans was evaluated by dose metrics to target volumes and critical brain structures. Expected clinical benefit of DP plans was assessed by tumor control probability. The DP plans were compared to standard radiotherapy plans.ResultsThe conformity of the DP plans was >90%. Compared to the standard plans, DP (1) did not affect dose delivered to organs at risk; (2) increased mean and maximum dose and improved minimum dose coverage for the target volumes; (3) reduced minimum dose within the radiotherapy treatment margins; (4) improved local tumor control probability within the target volumes for all patients.ConclusionsA multiparametric MRI model of GBM infiltration can enable conformal, feasible, and potentially beneficial dose painting radiotherapy plans.

ОЦЕНКА ЭФФЕКТИВНОСТИ ЛУЧЕВОЙ ТЕРАПИИ РАКА ГОЛОВЫ-ШЕИ НА ОСНОВЕ МОДЕЛИ ЛОКАЛЬНОГО КОНТРОЛЯ ОПУХОЛИ

Purpose: Evaluation of the expected effectiveness of radiation therapy based on models of the local tumor control probability (Tumor Control Probability – TCP) for the head-neck cancer. &#x0D; Material and methods: The study used data from 11 patients with locally advanced head-neck cancer (larynx, oropharynx, and oral cavity). For each patient two dosimetric treatment plans have been prepared: SIB-VMAT (70 Gy per tumor, 50 Gy per lymph nodes, 25 fractions) and SEQ-VMAT (70 Gy per tumor, 50 Gy per lymph nodes, 35 fractions). The developed plans were analyzed using A. Niemierko's TCP model with parameters obtained by B. Maciejewski (TCD50 = 70.26 Gy with a 49-day total treatment time), taking into account the dose–volume histograms and the total treatment time.&#x0D; Results: The developed plans ensured a high level of coverage (98–98 %) of the Clinical treatment volume (CTV) in all but one patient. The average TCP SIB-VMAT is 99.9 % due to the very short total treatment time. The average TCP for SEQ-VMAT is 61.0%. For one patient, both SIB-VMAT and SEQ-VMAT showed zero expected efficacy due to 95–95 % CTV coverage.&#x0D; Conclusion: The use of TCP model allows analyzing personalized treatment plans for patients and developing adaptive treatment regimens with an increase in the total dose, dose per fraction, and a decrease in the total treatment time.

Tumor control probability in hypofractionated radiotherapy as a function of total and hypoxic tumor volumes

Clinical studies in the hypofractionated stereotactic body radiotherapy (SBRT) have shown a reduction in the probability of local tumor control with increasing initial tumor volume. In our earlier work, we obtained and tested an analytical dependence of the tumor control probability (TCP) on the total and hypoxic tumor volumes using conventional radiotherapy model with the linear-quadratic (LQ) cell survival. In this work, this approach is further refined and tested against clinical observations for hypofractionated radiotherapy treatment schedules. Compared to radiotherapy with conventional fractionation schedules, simulations of hypofractionated radiotherapy may require different models for cell survival and the oxygen enhancement ratio (OER). Our TCP simulations in hypofractionated radiotherapy are based on the LQ model and the universal survival curve (USC) developed for the high doses used in SBRT. The predicted trends in local control as a function of the initial tumor volume were evaluated in SBRT for non-small cell lung cancer (NSCLC). Our results show that both LQ and USC based models cannot describe the TCP reduction for larger tumor volumes observed in the clinical studies if the tumor is considered completely oxygenated. The TCP calculations are in agreement with the clinical data if the subpopulation of radio-resistant hypoxic cells is considered with the volume that increases as initial tumor volume increases. There are two conclusions which follow from our simulations. First, the extent of hypoxia is likely a primary reason of the TCP reduction with increasing the initial tumor volume in SBRT for NSCLC. Second, the LQ model can be an acceptable approximation for the TCP calculations in hypofractionated radiotherapy if the tumor response is defined primarily by the hypoxic fraction. The larger value of OER in the hypofractionated radiotherapy compared to the conventional radiotherapy effectively extends the applicability of the LQ model to larger doses.

Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L

Head and neck squamous cell carcinoma (HNSCC) is often being diagnosed at an advanced stage, conferring a poor prognosis. The probability of local tumor control after radiotherapy depends on the eradication of cancer stem cells (CSCs) with activated DNA repair. This study provides evidence that the CSC-related transcription factor Oct4 contributes to HNSCC radioresistance by regulating DNA damage response and the CSC phenotype. Knockdown of Oct4 A isoform reduced self-renewal capacity in HNSCC and led to partial tumor cell radiosensitization caused by transcriptional downregulation of the cell cycle checkpoint kinases CHK1 and WEE1 and homologous recombination (HR) repair genes PSMC3IP and RAD54L. Besides, PARP inhibition with Olaparib selectively radiosensitized Oct4 A knockout, but not wild-type HNSCC cells. This finding links Oct4 A to the HR-mediated DNA repair mechanisms. In turn, knockdown of PSMC3IP and RAD54L reduced the HNSCC self-renewal capacity and clonogenic cell survival after irradiation, suggesting the interplay between DNA repair and the CSC phenotype. Similar to the effect of Oct4 knockdown, overexpression of Oct4 also resulted in significant HNSCC radiosensitization and increased DNA damage, suggesting that Oct4-dependent regulation of DNA repair depends on its fine-tuned expression. In line with this observation, HNSCC patients with high and low nuclear Oct4 expression at the invasive tumor front exhibited better loco-regional tumor control after postoperative radio(chemo)therapy compared to the intermediate expression subgroup. Thus, we found that the Oct4-driven transcriptional program plays a critical role in regulating HNSCC radioresistance, and a combination of radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors.

Development of a Model to Estimate the Association Between Delay in Cancer Treatment and Local Tumor Control and Risk of Metastases

The coronavirus disease 2019 (COVID-19) pandemic has led to treatment delays for many patients with cancer. While published guidelines provide suggestions on which cases are appropriate for treatment delay, there are no good quantitative estimates on the association of delays with tumor control or risk of new metastases. To develop a simplified mathematical model of tumor growth, control, and new metastases for cancers with varying doubling times and metastatic potential and to estimate tumor control probability (TCP) and metastases risk as a function of treatment delay interval. This decision analytical model describes a quantitative model for 3 tumors (ie, head and neck, colorectal, and non-small cell lung cancers). Using accepted ranges of tumor doubling times and metastatic development from the clinical literature from 2001 to 2020, estimates of tumor growth, TCP, and new metastases were analyzed for various treatment delay intervals. Risk estimates for potential decreases in local TCP and increases in new metastases with each interval of treatment delay. For fast-growing head and neck tumors with a 2-month treatment delay, there was an estimated 4.8% (95% CI, 3.4%-6.4%) increase in local tumor control risk and a 0.49% (0.47%-0.51%) increase in new distal metastases risk. A 6-month delay was associated with an estimated 21.3% (13.4-30.4) increase in local tumor control risk and a 6.0% (5.2-6.8) increase in distal metastases risk. For intermediate-growing colorectal tumors, there was a 2.1% (0.7%-3.5%) increase in local tumor control risk and a 2.7% (2.6%-2.8%) increase in distal metastases risk at 2 months and a 7.6% (2.2%-14.2%) increase in local tumor control risk and a 24.7% (21.9%-27.8%) increase in distal metastases risk at 6 months. For slower-growing lung tumors, there was a 1.2% (0.0%-2.8%) increase in local tumor control risk and a 0.19% (0.18%-0.20%) increase in distal metastases risk at 2 months, and a 4.3% (0.0%-10.6%) increase in local tumor control risk and a 1.9% (1.6%-2.2%) increase in distal metastases risk at 6 months. This study proposed a model to quantify the association of treatment delays with local tumor control and risk of new metastases. The detrimental associations were greatest for tumors with faster rates of proliferation and metastasis. The associations were smaller, but still substantial, for slower-growing tumors.

Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization

BackgroundThe probability of local tumor control after radiotherapy (RT) remains still miserably poor in pediatric rhabdomyosarcoma (RMS). Thus, understanding the molecular mechanisms responsible of tumor relapse is essential to identify personalized RT-based strategies. Contrary to what has been done so far, a correct characterization of cellular radioresistance should be performed comparing radioresistant and radiosensitive cells with the same isogenic background.MethodsClinically relevant radioresistant (RR) embryonal (RD) and alveolar (RH30) RMS cell lines have been developed by irradiating them with clinical-like hypo-fractionated schedule. RMS-RR cells were compared to parental isogenic counterpart (RMS-PR) and studied following the radiobiological concept of the “6Rs”, which stand for repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and radio-immuno-biology.ResultsRMS-RR cell lines, characterized by a more aggressive and in vitro pro-metastatic phenotype, showed a higher ability to i) detoxify from reactive oxygen species; ii) repair DNA damage by differently activating non-homologous end joining and homologous recombination pathways; iii) counteract RT-induced G2/M cell cycle arrest by re-starting growth and repopulating after irradiation; iv) express cancer stem-like profile. Bioinformatic analyses, performed to assess the role of 41 cytokines after RT exposure and their network interactions, suggested TGF-β, MIF, CCL2, CXCL5, CXCL8 and CXCL12 as master regulators of cancer immune escape in RMS tumors.ConclusionsThese results suggest that RMS could sustain intrinsic and acquire radioresistance by different mechanisms and indicate potential targets for future combined radiosensitizing strategies.

A Dose-Response Model of Local Tumor Control Probability After Stereotactic Radiosurgery for Brain Metastases Resection Cavities

PurposeRecent randomized controlled trials evaluating stereotactic surgery (SRS) for resected brain metastases question the high rates of local control previously reported in retrospective studies. Tumor control probability (TCP) models were developed to quantify the relationship between radiation dose and local control after SRS for resected brain metastases. Methods and MaterialsPatients with resected brain metastases treated with SRS were evaluated retrospectively. Melanoma, sarcoma, and renal cell carcinoma were considered radio-resistant histologies. The planning target volume (PTV) was the region of enhancement on T1 post-gadolinium magnetic resonance imaging plus a 2-mm uniform margin. The primary outcome was local recurrence, defined as tumor progression within the resection cavity. Cox regression evaluated predictors of local recurrence. Dose-volume histograms for the PTV were obtained from treatment plans and converted to 3-fraction equivalent doses (α/β = 12 Gy). TCP models evaluated local control at 1-year follow-up as a logistic function of dose-volume histogram data. ResultsAmong 150 cavities, 41 (27.3%) were radio-resistant. The median PTV volume was 14.6 mL (range, 1.3-65.3). The median prescription was 21 Gy (range, 15-25) in 3 fractions (range, 1-5). Local control rates at 12 and 24 months were 86% and 82%. On Cox regression, larger cavities (PTV > 12 cm3) predicted increased risk of local recurrence (P = .03). TCP modeling demonstrated relationships between improved 1-year local control and higher radiation doses delivered to radio-resistant cavities. Maximum PTV doses of 30, 35, and 40 Gy predicted 78%, 89%, and 94% local control among all radio-resistant cavities, versus 69%, 79%, and 86% among larger radio-resistant cavities. ConclusionsAfter SRS for resected brain metastases, larger cavities are at greater risk of local recurrence. TCP models suggests that higher radiation doses may improve local control among cavities of radio-resistant histology. Given maximum tolerated doses established for single-fraction SRS, fractionated regimens may be required to optimize local control in large radio-resistant cavities.

Correlating Dose Variables with Local Tumor Control in Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Modeling Study on 1500 Individual Treatments

Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription. We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BEDmin); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BEDmax); and (3) the average between near-minimum and near-maximum doses (yielding BEDave). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion. There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BEDave was the best predictor of risk of local recurrence, and a model based on BEDmin had substantially less evidential support. In univariable logistic regression, the model based on BEDave also performed best. Multivariable classification using fast and frugal trees revealed BEDmax to be the most important predictor, followed by BEDave. BEDave was generally better correlated with tumor control probability than either BEDmax or BEDmin. Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation.

Radiobiological Evaluation of Dosimetric Plans for Stereotactic Radiotherapy for Prostate Cancer According to Fractionation Regimen

Objective. To determine the most effective irradiation regimen (total dose and dose per fraction) for hypofractionated treatment for prostate carcinomas according the TCP/NTCP radiobiological criteria.Material and methods. Using the tomographic information of five patients with low-risk prostate adenocarcinoma as an example, the authors devised dosimetric radiation therapy plans using the volumetric modulated arc therapy (VMAT) procedure. They considered the range of total doses of 33.5 to 38 Gy administered in 4 and 5 fractions. Based on the equivalent uniform dose concept proposed by A. Niemierko and on the computed differential dose volume histograms, the investigators modeled local tumor control probability (TCP) values, by taking into account the uncertainties of main radiobiological parameters, and estimated normal tissue complication probabilities (NTCP) for the anterior rectal wall as the organ most at risk of irradiation. An effective dosimetric plan was selected according to the UTCP criterion and the probability of complication-free tumor control, i.e. TCP (1 – NTCP).Results. The results of modeling the UTCP criterion show that with a higher total dose, the TCP value increases and so does the NTCP value, therefore the optimal radiation therapy plans are to irradiate with a total dose of 34 Gy over 4 fractions or with a dose of 36–37 Gy over 5 fractions. The difference between the fractionation regimens is that the UTCP value is achieved with a higher TCP value over 4 fractions and with a lower load on the rectal wall over 5 fractions.Conclusion. The choice of a specific fractionation regimen should be determined from the calculated values of differential dose volume histograms for each patient, as well as from radiobiological criteria, such as TCP, NTCP and UTCP.

A Dose-Response Model of Local Tumor Control Probability after Stereotactic Radiosurgery for Brain Metastases Resection Cavities

A Dose-Response Model of Local Tumor Control Probability after Stereotactic Radiosurgery for Brain Metastases Resection Cavities

Determinants for local tumour control probability after radiotherapy of anal cancer

Background and purposeAnal squamous cell carcinoma is primarily treated with radiotherapy (RT), but the optimal RT dose for anal tumours of different sizes is not known. The purpose of this study was to identify determinants for local tumour control probability (LTCP). Material and methodsFrom a large Nordic database 901 patients who received RT for anal cancer between 2000 and 2007 were selected. LTCP was analysed in a series of uni- and multivariable regression analyses. ResultsHigher RT dose, female gender and addition of chemotherapy were associated with higher LTCP whereas increasing tumour size, tumour invasiveness (stage T4) and lymph node metastases (N+) were associated with lower LTCP. Male patients needed approximately 10 Gy higher RT dose than female patients for similar LTCP. The addition of chemotherapy corresponded to 5–10 Gy RT dose. ConclusionsOur results basically support current guidelines recommending: (1) lower RT dose in small tumours (<4 cm), (2) higher RT dose larger tumours and in stages T4 and /or N+, (3) Chemo should be used in combination with RT. These results will hopefully constitute the basis for future trials, aiming at individualized RT dosing in patients with anal cancer.

Application of intensity-modulated radiation therapy in the treatment of nasopharyngeal carcinoma.

The objective of the present study was to investigate the application values of the intensity-modulated radiation therapy (IMRT) and the three-dimensional conformal radiation therapy (3D-CRT) in the treatment of nasopharyngeal carcinoma (NPC). A total of 124 patients diagnosed with nasopharyngeal carcinomas were included into the study and randomly divided into the control group and the observation group, with 62 patients in each group. The 3D-CRT combined with postoperative chemotherapy were performed on the control group and the observation group received IMRT combined with postoperative chemotherapy, and then were followed up for a median duration of 25.5 months. Comparison of the survival analysis of the two groups showed no differences between them in terms of the total effective rate and effectiveness (P>0.05), or radiotherapy complications (P>0.05). In addition, no significant differences between the two groups were found in the follow-up local tumor control probability (TCP), regional lymph node control rate, distant metastasis-free rate, tumor-free survival rate, recurrence rate and overall survival rate (P>0.05). Furthermore, there was no difference between the two groups in the overall score of quality of life (P>0.05). The present study concludes that the IMRT and the 3D-CRT have almost the same short-term and long-term clinical effects in the treatment of nasopharyngeal carcinoma and both of them have high effectiveness and safety.