Tumor Control Probability Data Research Articles

Modeling of the resensitization effect on carbon-ion radiotherapy for stage I non-small cell lung cancer

Objective. To investigate the effect of redistribution and reoxygenation on the 3-year tumor control probability (TCP) of patients with stage I non-small cell lung cancer (NSCLC) treated with carbon-ion radiotherapy. Approach. A meta-analysis of published clinical data of 233 NSCLC patients treated by carbon-ion radiotherapy under 18-, 9-, 4-, and single-fraction schedules was conducted. The linear-quadratic (LQ)-based cell-survival model incorporating the radiobiological 5Rs, radiosensitivity, repopulation, repair, redistribution, and reoxygenation, was developed to reproduce the clinical TCP data. Redistribution and reoxygenation were regarded together as a single phenomenon and termed ‘resensitization’ in the model. The optimum interval time between fractions was investigated for each fraction schedule using the determined model parameters. Main results. The clinical TCP data for 18-, 9-, and 4-fraction schedules were reasonably reproduced by the model without the resensitization effect, whereas its incorporation was essential to reproduce the TCP data for all fraction schedules including the single fraction. The curative dose for the single-fraction schedule was estimated to be 49.0 Gy (RBE), which corresponds to the clinically adopted dose prescription of 50.0 Gy (RBE). For 18-, 9-, and 4-fraction schedules, a 2-to-3-day interval is required to maximize the resensitization effect during the time interval. In contrast, the single-fraction schedule cannot benefit from the resensitization effect, and the shorter treatment time is preferable to reduce the effect of sub-lethal damage repair during the treatment. Significance. The LQ-based cell-survival model incorporating the radiobiological 5Rs was developed and used to evaluate the effect of the resensitization on clinical results of NSCLC patients treated with hypo-fractionated carbon-ion radiotherapy. The incorporation of the resensitization into the cell-survival model improves the reproducibility to the clinical TCP data. A shorter treatment time is preferable in the single-fraction schedule, while a 2-to-3-day interval between fractions is preferable in the multi-fraction schedules for effective treatments.

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.

Optimal hypofractionated radiation therapy schemes for early-stage hepatocellular carcinoma

PurposeStereotactic body radiation therapy (SBRT) has been emerging as an efficacious and safe treatment modality for early-stage hepatocellular carcinoma (HCC), but optimal fractionation regimens are unknown. This study aims to analyze published clinical tumor control probability (TCP) data as a function of biologically effective dose (BED) and to determine radiobiological parameters and optimal fractionation schemes for SBRT and hypofractionated radiation therapy of early-stage HCC. Material and MethodsClinical 1- to 5-year TCP data of 4313 patients from 41 published papers were collected for hypofractionated radiation therapy at 2.5–4.5 Gy/fraction and SBRT of early-stage HCC. BED was calculated at isocenter using three representative radiobiological models developed per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. Radiobiological parameters were determined from a fit to the TCP data using the least χ2 method with one set of model parameters regardless of tumor stages or Child-Pugh scores A and B. ResultsThe fits to the clinical TCP data for SBRT of early-stage HCC found consistent α/β ratios of about 14 Gy for all three radiobiological models. TCP increases sharply with BED and reaches an asymptotic maximal plateau, which results in optimal fractionation schemes of least doses to achieve asymptotic maximal tumor control for SBRT and hypofractionated radiation therapy of early-stage HCC that are found to be model-independent. ConclusionFrom the fits to the clinical TCP data, we presented the first determination of radiobiological parameters and model-independent optimal fractionation regimens in 1–20 fractions to achieve maximal tumor control whenever safe for SBRT and hypofractionated radiation therapy of early-stage HCC. The determined optimal fractionation schemes agree well with clinical practice for SBRT of early-stage HCC. However, most existing hypofractionated radiation therapy schemes of 3–5 Gy/fraction are not optimal, higher doses are required to maximize tumor control, further validation of these findings is essential with clinical TCP data.

Proton versus photon therapy for high-risk prostate cancer with dose escalation of dominant intraprostatic lesions: a preliminary planning study.

This study aimed to investigate the feasibility of safe-dose escalation to dominant intraprostatic lesions (DILs) and assess the clinical impact using dose-volume (DV) and biological metrics in photon and proton therapy. Biological parameters defined as late grade ≥ 2 gastrointestinal (GI) and genitourinary (GU) derived from planned (D P) and accumulated dose (D A) were utilized. In total, 10 patients with high-risk prostate cancer with multiparametric MRI-defined DILs were investigated. Each patient had two plans with a focal boost to the DILs using intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT). Plans were optimized to obtain DIL coverage while respecting the mandatory organ-at-risk constraints. For the planning evaluation, DV metrics, tumor control probability (TCP) for the DILs and whole prostate excluding the DILs (prostate-DILs), and normal tissue complication probability (NTCP) for the rectum and bladder were calculated. Wilcoxon signed-rank test was used for analyzing TCP and NTCP data. IMPT achieved a higher Dmean for the DILs compared to VMAT (IMPT: 68.1 GyRBE vs. VMAT: 66.6 Gy, p < 0.05). Intermediate-high rectal and bladder doses were lower for IMPT (p < 0.05), while the high-dose region (V60 Gy) remained comparable. IMPT-TCP for prostate-DIL were higher compared to VMAT (IMPT: 86%; α/β = 3, 94.3%; α/β = 1.5 vs. VMAT: 84.7%; α/β = 3, 93.9%; α/β = 1.5, p < 0.05). Likewise, IMPT obtained a moderately higher DIL TCP (IMPT: 97%; α/β = 3, 99.3%; α/β = 1.5 vs. VMAT: 95.9%; α/β = 3, 98.9%; α/β = 1.5, p < 0.05). Rectal D A-NTCP displayed the highest GI toxicity risk at 5.6%, and IMPT has a lower GI toxicity risk compared to VMAT-predicted Quantec-NTCP (p < 0.05). Bladder D P-NTCP projected a higher GU toxicity than D A-NTCP, with VMAT having the highest risk (p < 0.05). Dose escalation using IMPT is able to achieve a high TCP for the DILs, with the lowest rectal and bladder DV doses at the intermediate-high-dose range. The reduction in physical dose was translated into a lower NTCP (p < 0.05) for the bladder, although rectal toxicity remained equivalent.

Optimal Radiation Therapy Fractionation Regimens for Early-Stage Non-Small Cell Lung Cancer

A series of radiobiological models were developed to study tumor control probability (TCP) for stereotactic body radiation therapy (SBRT) of early-stage non-small cell lung cancer (NSCLC) per the Hypofractionated Treatment Effects in the Clinic (HyTEC) working group. This study was conducted to further validate 3 representative models with the recent clinical TCP data ranging from conventional radiation therapy to SBRT of early-stage NSCLC and to determine systematic optimal fractionation regimens in 1 to 30 fractions for radiation therapy of early-stage NSCLC that were found to be model-independent. Recent clinical 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data of 9808 patients from 56 published papers were collected for radiation therapy of 2 to 4 Gy per fraction and SBRT of early-stage NSCLC. This data set nearly triples the original HyTEC sample, which was used to further validate the HyTEC model parameters determined from a fit to the clinical TCP data. TCP data from the expanded data set are well described by the HyTEC models with α/β ratios of about 20 Gy. TCP increases sharply with biologically effective dose and reaches an asymptotic maximal plateau, which allows us to determine optimal fractionation schemes for radiation therapy of early-stage NSCLC. The HyTEC radiobiological models with α/β ratios of about 20 Gy determined from the fits to the clinical TCP data for SBRT of early-stage NSCLC describe the recent TCP data well for both radiation therapy of 2 to 4 Gy per fraction and SBRT dose and fractionation schemes of early-stage NSCLC. A steep dose response exists between TCP and biologically effective dose, and TCP reaches an asymptotic maximum. This feature results in model-independent optimal fractionation regimens determined whenever safe for SBRT and hypofractionated radiation therapy of early-stage NSCLC in 1 to 30 fractions to achieve asymptotic maximal tumor control, and T2 tumors require slightly higher optimal doses than T1 tumors. The proposed optimal fractionation schemes are consistent with clinical practice for SBRT of early-stage NSCLC.

Individualized Re-Irradiation Dose for Recurrent Nasopharyngeal Carcinoma Based on Outcome Modeling

The normal tissue toxicities such as temporal lobe necrosis, trismus and massive hemorrhage are a serious concern for re-irradiation of recurrent nasopharyngeal carcinoma (rNPC). This study explores a method to determine the optimal and patient-specific prescription dose for rNPC based on a quantitative consideration of normal tissue toxicity probability (NTCP) and tumor control probability (TCP). It has been reported that the total tolerable biologically effective dose (BED) calculated with α/β of 3 Gy (BEDmax3Gy) after two radiation treatments for rNPC can be higher than the tolerable BED of the initial radiation treatment, indicating normal tissue repair from radiation damage of the initial treatment. For example, BEDmax3Gy corresponding to 20% NTCP could be 129% the tolerable BED of the initial radiation treatment. Such observation can be described by the following expression: BED23Gy=BEDmax3Gy(1-BED13Gy/BEDmax3Gy)1/(r+1), where r=1.5+e0.5(τ-1) and τ is the time interval in year (gap) between two radiation treatments. BED13Gy and BED23Gy are BEDs of the initial and second radiation treatment. On the other hand, the multivariate analysis of TCP data from 295 rNPC patients revealed that the gap was a significant factor affecting TCP. The longer the gap, the better the tumor controls. A TCP model, called tumor regrowth-gap model, assuming that tumor regrowth after the initial treatment leads recurrence, was developed to investigate the TCP dependence on the time interval between the two treatment courses. The model parameters were determined by the TCP data of the 295 recurrent NPC patients and validated by another independent data set of 47 rNPC patients. Model fitting showed the prescribed re-irradiation dose and the speed of tumor cell regrowth significantly affected TCP of rNPC patients. The faster the tumor regrowth the earlier the recurrence and the poorer the clinic outcome of re-irradiation. The tumor BED of the second treatment (BED210Gy) that leads to 20% NTCP was found to be between 48 Gy to 58 Gy depending on the recurrence time, which corresponds to physical doses of 57 to 68 in 2 Gy per fraction. With the extracted model parameters, TCP at 5 years for irradiation of the rNPC patients were predicted based on allowable combination of BED210Gy and gap for a NTCP<20%. Assume that the prescription dose of the initial treatment is 70 Gy in 2 Gy per fraction.Abstract 1109; Tableτ (yr)0.51.01.52.02.53.03.54.04.55.05.56.0BED2 10 Gy (Gy)5887899193949596568083858890929395547073778184878991925259626670757882858789504850535762677276808386483940404348535964697478814629303134394450566166717544202222252935404652586368 Open table in a new tab The dependence of TCP/NTCP on BED and gap was established for re-irradiation of the rNPC. The model along with the extracted tumor-specific radiobiological parameters may be used to optimize re-irradiation dose and/or fractionation scheme for individual patients with rNPC.

An analysis of tumor control probability of stereotactic body radiation therapy for lung cancer with a regrowth model

We report a modeling study of tumor response after stereotactic body radiation therapy (SBRT) for early-stage non-small-cell lung carcinoma using published clinical data with a regrowth model.A linear-quadratic inspired regrowth model was proposed to analyze the tumor control probability (TCP) based on a series of published data of SBRT, in which a tumor is controlled for an individual patient if number of tumor cells is smaller than a critical value Kcr. The regrowth model contains radiobiological parameters such as α, α/β the potential doubling time Tp. This model also takes into account the heterogeneity of tumors and tumor regrowth after radiation treatment. The model was first used to fit TCP data from a single institution. The extracted fitting parameters were then used to predict the TCP data from another institution with a similar dose fractionation scheme. Finally, the model was used to fit the pooled TCP data selected from 48 publications available in the literature at the time when this manuscript was written.Excellent agreement between model predictions and single-institution data was found and the extracted radiobiological parameters were α = 0.010 ± 0.001 Gy−1, α /β = 21.5 ± 1.0 Gy and Tp = 133.4 ± 7.6 d. These parameters were α = 0.072 ± 0.006 Gy−1, α/β = 15.9 ± 1.0 Gy and Tp = 85.6 ± 24.7 d when extracted from multi-institution data. This study shows that TCP saturates at a BED of around 120 Gy. A few new dose-fractionation schemes were proposed based on the extracted model parameters from multi-institution data.It is found that the regrowth model with an α/β around 16 Gy can be used to predict the dose response of lung tumors treated with SBRT. The extracted radiobiological parameters may be useful for comparing clinical outcome data of various SBRT trials and for designing new treatment regimens.

TU‐A‐BRD‐01: Outcomes of Hypofractionated Treatments – Initial Results of the WGSBRT

Stereotactic Body Radiation Therapy (SBRT) has emerged in recent decades as a treatment paradigm that is becoming increasingly important in clinical practice. Clinical outcomes data are rapidly accumulating. Although published relations between outcomes and dose distributions are still sparse, the field has progressed to the point where evidence‐based normal tissue dose‐volume constraints, prescription strategies, and Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) models can be developed.The Working Group on SBRT (WGSBRT), under the Biological Effects Subcommittee of AAPM, is a group of physicists and physicians working in the area of SBRT. It is currently performing critical literature reviews to extract and synthesize usable data and to develop guidelines and models to aid with safe and effective treatment. The group is investigating clinically relevant findings from SBRT in six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal.In this session of AAPM 2014, interim results are presented on TCP for lung and liver, NTCP for thoracic organs, and radiobiological foundations:• Lung TCP: Detailed modeling of TCP data from 118 published studies on early stage lung SBRT investigates dose response and hypothesized mechanisms to explain the improved outcomes of SBRT. This is presented from the perspective of a physicist, a physician, and a radiobiologist.• Liver TCP: For primary and metastatic liver tumors, individual patient data were extracted from published reports to examine the effects of biologically effective dose on local control.• Thoracic NTCP: Clinically significant SBRT toxicity of lung, rib / chest wall and other structures are evaluated and compared among published clinical data, in terms of risk, risk factors, and safe practice.• Improving the clinical utility of published toxicity reports from SBRT and Hypofractionated treatments. What do we want, and how do we get it? Methods and problems of synthesizing data from published reports.Learning Objectives: Common SBRT fractionation schemes and current evidence for efficacy. Evidence for normal tissue tolerances in hypofractionated treatments. Clinically relevant radiobiological effects at large fraction sizes.

Onset Time of Tumor Repopulation for Cervical Cancer: First Evidence From Clinical Data

Accelerated tumor repopulation has significant implications in low-dose rate (LDR) brachytherapy. Repopulation onset time remains undetermined for cervical cancer. The purpose of this study was to determine the onset time of accelerated repopulation in cervical cancer, using clinical data. The linear quadratic (LQ) model extended for tumor repopulation was used to analyze clinical data and magnetic resonance imaging-based three-dimensional tumor volumetric regression data from 80 cervical cancer patients who received external beam radiotherapy (EBRT) and LDR brachytherapy. The LDR dose was converted to EBRT dose in 1.8-Gy fractions by using the LQ formula, and the total dose ranged from 61.4 to 99.7 Gy. Patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least χ(2) method was used to fit the TCP data with two free parameters: onset time (T(k)) of accelerated repopulation and number of clonogens (K), while other LQ model parameters were adopted from the literature, due to the limited patient data. Among the 11 patient groups, TCP varied from 33% to 100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment duration were associated with higher TCP. Using the LQ model, we achieved the best fit with onset time T(k) of 19 days and K of 139, with uncertainty ranges of (11, 22) days for T(k) and (48, 1822) for K, respectively. This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from clinical data by using the LQ model. Our study verifies the fact that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted.

Dose volume histogram analysis and comparison of different radiobiological models using in-house developed software

The purpose of this study is to compare Lyman-Kutcher-Burman (LKB) model versus Niemierko model for normal tissue complication probability (NTCP) calculation and Niemierko model versus Poisson-based model for tumor control probability (TCP) calculation in the ranking of different treatment plans for a patient undergoing radiotherapy. The standard normal tissue tolerance data were used to test the NTCP models. LKB model can reproduce the same complication probability data of normal tissue response on radiation, whereas Niemierko model cannot reproduce the same complication probability. Both Poisson-based and Niemierko models equally reproduce the same standard TCP data in testing of TCP. In case of clinical data generated from treatment planning system, NTCP calculated using LKB model was found to be different from that calculated using Niemierko model. When the fractionation effect was considered in LKB model, the calculated values of NTCPs were different but comparable with those of Niemierko model. In case of TCP calculation using these models, Poisson-based model calculated marginally higher control probability as compared to Niemierko model.

Population TCP estimators in case of heterogeneous irradiation: A new discussion of an old problem

Purpose. To investigate the capacity of two phenomenological expressions to describe the population tumor response in case of a heterogeneous irradiation of the tumor. The generalization of the individual tumor control probability (TCP) models to include the case of a heterogeneous irradiation is a trivial problem. However, an analytical solution that results in a closed form population TCP formula for the heterogeneous case is, unfortunately, a very complex mathematical problem. Therefore we applied a numerical approach to the problem. Method. Pseudo-experimental data sets are constructed through the generation of dose distributions and population TCP data obtained by a numerical solution of a multi-dimensional integral over an individual TCP model. The capacity of the following two phenomenological – Poisson and equivalent uniform dose (EUD) based – TCP expressions:to describe the population tumor response in case of heterogeneous irradiation is investigated through their fitting to the psuedo-experimental data sets. Results and conclusions. While both expressions produce statistically acceptable fits to the pseudo-experimental data within 2% TCP error band, the use of the second expression is preferable since it produces considerably better fits to the data sets.

Analysis of tumor control probability (TCP) and normal tissue complication probability (NTCP) in 40 prostate cancer patients treated with 2 different techniques of 3D-conformal radiation therapy (3D-CRT)

Purpose: To compare 2 regimens of 3D-CRT (3-field vs 6-field technique) in the treatment of prostate cancer, using TCP and NTCP data. Materials & Methods: Between October and December 1997, 20 consecutive patients with clinically localized adenocarcinoma of the prostate (4 T1, 9 T2, 7 T3) were treated with 3D-CRT 3-field technique. For the purpose of this study the records of 20 patients matched for tumor stage (5 T1, 9 T2, 6 T3) and treated with 3D-CRT 6-field technique, were analyzed and served as a basis for comparison. With the 3-field technique, the patients were simulated with rectum and bladder empty in a supine position using custom-made polyurethane foam or thermoplastic casts as immobilization devices. An anterior field (0) and two wedged posterior oblique fields (110 and 250 °) were devised. In order to minimize the dose delivered to the anterior rectal wall and despite a less homogenous dose distribution within the target, the wedges were inserted with the thick end toward the midline. Non-uniform margins were applied around the outline of the target volume, that is, 1 cm towards the rectal wall and 1.5 cm towards the bladder anteriorly and also for the upper and lower portal margins. The shaping of the beam apertures was realized by conventional cerrobend blocks. The total target dose was prescribed at the ICRU point and was 76 Gy for the prostate delivered by a 15 MV linear accelerator in 38 fractions and 56 days (mean). The seminal vesicles were excluded at 70 Gy. The 6-field technique was different only in positioning of the patient (prone) and arrangement of portals (45 °, 90, 135 °, 225*, 270*, 315*). For the calculation of the NTCP values regarding the bladder and rectum we have employed the Lyman's empirical model. The cumulative dose-volume histograms were reduced according to the effective volume model introduced by Kutcher and Burman. Radiobiological data published by Emami was used in this analysis. The TCP calculation was made according to Goitein's model. The mean TCP and NTCP values over the two groups were compared using a pooled two sample t-test. The log percentages were used to ensure that the normality assumptions were valid. Results: TCP values obtained with the two techniques were similar: mean value equals 98.7 for the 3-field technique (range: 97.6-99.4), 98.6 for the 6-field technique (range: 97.5-99.5), meaning a good target coverage with both techniques; p= 0.27, that means no evidence of difference between the two techniques for target coverage. NTCP values were: bladder NTCP 0.96 for 3-field (range: 0.02-4.99) and 0.91 for 6-field (range: 0.02-4.48) (p=0.67), rectum NTCP 7.6 for 3field (range: 2.7-16.9) and 5.7 for 6-field (range: 1.6-11.9) (p=0.051). There is no evidence of difference between the two techniques for bladder complication, but there may be some evidence of difference between the two groups for rectum complications. Conclusions: The two techniques yielded similar results in terms of TCP and bladder NTCP. In terms of rectum NTCP, there was a slight difference in favour of the 6-field technique. Acute toxicity was similar in either groups, but longer follow-up is needed to evaluate the relationship between the mathematical modelling and the rate of late toxicity. The difficulty in extrapolating data from other institutions when calculating TCP and NTCP prompted us to create our own database to evaluate the validity and the predictibility of these mathematical models, considering that different DVH calculation algorithms are usually applied in each center.