Lyman Normal Tissue Complication Probability Research Articles

Estimating the risk of major adverse cardiac events following radiotherapy for left breast cancer using a modified generalized Lyman normal-tissue complication probability model

BackgroundWe introduced an adapted Lyman normal-tissue complication probability (NTCP) model, incorporating clinical risk factors and censored time-to-event data, to estimate the risk of major adverse cardiac events (MACE) following left breast cancer radiotherapy (RT). Materials and methodsClinical characteristics and MACE data of 1100 women with left-side breast cancer receiving postoperative RT from 2005 to 2017 were retrospectively collected. A modified generalized Lyman NTCP model based on the individual left ventricle (LV) equivalent uniform dose (EUD), accounting for clinical risk factors and censored data, was developed using maximum likelihood estimation. Subgroup analysis was performed for low-comorbidity and high-comorbidity groups. ResultsOver a median follow-up 7.8 years, 64 patients experienced MACE, with higher mean LV dose in affected individuals (4.1 Gy vs. 2.9 Gy). The full model accounting for clinical factors identified D50 = 43.3 Gy, m = 0.59, and n = 0.78 as the best-fit parameters. The threshold dose causing a 50 % probability of MACE was lower in the high-comorbidity group (D50 = 30 Gy) compared to the low-comorbidity group (D50 = 45 Gy). Predictions indicated that restricting LV EUD below 5 Gy yielded a 10-year relative MACE risk less than 1.3 and 1.5 for high-comorbidity and low-comorbidity groups, respectively. ConclusionPatients with comorbidities are more susceptible to cardiac events following breast RT. The proposed modified generalized Lyman model considers nondosimetric risk factors and addresses incomplete follow-up for late complications, offering comprehensive and individualized MACE risk estimates post-RT.

The Lyman Normal Tissue Complication Probability Model and Risk Prediction for Temporal Lobe Injury after Re-Irradiation in Patients with Recurrent Nasopharyngeal Carcinoma

The risk of temporal lobe injury (TLI) in recurrent nasopharyngeal carcinoma (rNPC) patients with intensity-modulated radiation therapy (IMRT) is high. We aimed to construct the normal tissue complication probability (NTCP) model for TLI of rNPC and establish a risk predictive model. We retrospectively analyzed 103 patients with rNPC who had received two courses of IMRT in our institution. The 206 temporal lobes (TLs) of these patients were randomly divided into a training (n = 144) and validation group (n = 62). We determined the mean value of the following parameters to construct the Lyman NTCP model: TD50(1) (the dose with a 50% probability of complications to an organ when all volumes are irradiated), m [steepness of the dose-response at TD50(1)], and n (the parameter related to volume effect). The most predictive dosimetric parameter and clinical variables were integrated in Cox proportional hazards models. A nomogram was developed for predicting risk of TLs. The parameters of the fitted NTCP model were TD50(1) = 107.84 Gy (95% confidence interval (CI), [97.15, 118.54]), m = 0.16 (95% CI, [0.14, 0.19]), and n = 0.04 (95% CI, [0.01, 0.06]). The cumulative dose delivered to 0.1 cm3 of temporal lobe volume (D0.1cc-c) was the most predictive dosimetric parameter for TLI. The Kaplan-Meier curves showed a significant difference in 2-year TLI-free survival among different risk groups according to the total score of nomograms. The TD50(1) of TLI in patients with rNPC is 107.84 Gy in Lyman NTCP model. The nomogram model can accurately predict the risk of TLI for individual.

Combining Step-and-Shoot Intensity Modulated Radiation Therapy Concomitant Boost to Tumor Bed and 3D Breast Field-in-Field Plans for Hypofractionated Breast Radiotherapy

<h3>Purpose/Objective(s)</h3> To investigate the efficacy and safety of step-and-shoot intensity modulated radiation therapy (IMRT) concomitant boost (CB) to tumor bed (TB) combined with 3D breast field-in-field (FIF) plans for hypofractionated breast radiotherapy. <h3>Materials/Methods</h3> We initiated prospective cohort study since January, 2020. The patients with early-stage breast cancer or breast ductal carcinoma in situ who received breast-conserving surgery underwent sixteen-fraction treatment. All received prescribed dose of 40 Gy 3D FIF plans to breast, CB with 8 Gy to TB by IMRT. We applied the identical contours and PTV coverage to compare the original plans with the re-plans using conventional fractions of breast FIF followed by en face electron beams to TB on the same patients. Plan quality including maximum dose, RTOG conformal index (CI) and homogeneity index (HI) of PTV_TB, mean dose and volumes irradiated to doses of 5 Gy (V₅) of heart and V₂₀ of ipsilateral lung, in addition to acute toxicity and any recurrence were evaluated. Lyman normal tissue complication probability (NTCP) model for moderate to severe breast fibrosis established by Cambridge and EORTC trials was also calculated. Paired sample t-test and Wilcoxon signed-rank test were used. <h3>Results</h3> Thirty patients with sixty treatment plans were reviewed. The majority (19/30) were pathological prognostic stage I breast cancer and half of the patients were left-sided diseases. No patient experienced more than grade 2 acute toxicity. No recurrence was observed during the follow-up. Mean HI (D₂-D₉₈/D_p × 100; where D₂ = minimum dose to the 2% of the target volume, D₉₈ = minimum dose to the 98% of the target volume, and D_p = prescribed dose) of PTV_TB is 9.4 vs. 18.5 (<i>P</i> < .05). Maximum dose divided by reference dose was also lower in the CB group by 2.9% (<i>P</i> < .05). Mean CI is 1.45 in the CB group compared to 1.63 in the conventional fraction plans (<i>P</i> = .07). In terms of EQD2, mean dose and V₅ of heart for left-sided breast cancer are similar (<i>P</i> = .12 and 0.10). Besides, mean dose and V₂₀ of ipsilateral lung are comparable (<i>P</i> = .26 and 0.43). NTCP for breast fibrosis were all lower in the CB group (Mean: 20.02% vs. 22.13%; <i>P</i> < .05). <h3>Conclusion</h3> Hypofractionated breast radiotherapy combing 3D FIF plans and IMRT CB to TB decreased breast moderate to severe fibrosis by Lyman NTCP model and improved homogenous dose distributions without excessive dose to normal tissue, when compared to conventional fractions using FIF and electron beams. It may reduce the toxicity, and is also labor-saving for patients, radiation oncologists and staff.

Dosimetric predictors and Lyman normal tissue complication probability model of hematological toxicity in cervical cancer patients with treated with pelvic irradiation.

PurposeTo identify dosimetric parameters associated with acute hematological toxicity (HT) and identify the corresponding normal tissue complication probability (NTCP) model in cervical cancer patients receiving helical tomotherapy (Tomo) or fixed‐field intensity‐modulated radiation therapy (ff‐IMRT) in combination with chemotherapy, that is, concurrent chemoradiotherapy (CCRT) using the Lyman–Kutcher–Burman normal tissue complication probability (LKB‐NTCP) model.MethodsData were collected from 232 cervical cancer patients who received Tomo or ff‐IMRT from 2015 to 2018. The pelvic bone marrow (PBM) (including the ilium, pubes, ischia, acetabula, proximal femora, and lumbosacral spine) was contoured from the superior boundary (usually the lumbar 5 vertebra) of the planning target volume (PTV) to the proximal end of the femoral head (the lower edge of the ischial tubercle). The parameters of the LKB model predicting ≥grade 2 hematological toxicity (Radiation Therapy Oncology Group [RTOG] grading criteria) (TD 50(1), m, and n) were determined using maximum likelihood analyses. Univariate and multivariate logistic regression analyses were used to identify correlations between dose–volume parameters and the clinical factors of HT.ResultsIn total, 212 (91.37%) patients experienced ≥grade 2 hematological toxicity. The fitted normal tissue complication probability model parameters were TD 50(1) = 38.90 Gy (95%CI, [36.94, 40.96]), m = 0.13 (95%CI [0.12, 0.16]), and n = 0.04 (95%CI [0.02, 0.05]). Per the univariate analysis, the NTCP (the use of LKB‐NTCP with the set of model parameters found, p = 0.023), maximal PBM dose (p = 0.01), mean PBM dose (p = 0.021), radiation dose (p = 0.001), and V 16–53 (p < 0. 05) were associated with ≥grade 2 HT. The NTCP (the use of LKB‐NTCP with the set of model parameters found, p = 0.023; AUC = 0.87), V 16, V 17, and V 18 ≥ 79.65%, 75.68%, and 72.65%, respectively (p < 0.01, AUC = 0.66∼0.68), V 35 and V 36 ≥ 30.35% and 28.56%, respectively (p < 0.05; AUC = 0.71), and V 47 ≥ 13.43% (p = 0.045; AUC = 0.80) were significant predictors of ≥grade 2 hematological toxicity from the multivariate logistic regression analysis.ConclusionsThe volume of the PBM of patients treated with concurrent chemoradiotherapy and subjected to both low‐dose (V 16–18) and high‐dose (V 35,36 and V 47) irradiation was associated with hematological toxicity, depending on the fractional volumes receiving the variable degree of dosage. The NTCP were stronger predictors of toxicity than V 16–18, V 35, 36, and V 47. Hence, avoiding radiation hot spots on the PBM could reduce the incidence of severe HT.

Correlation of clinical outcome, radiobiological modeling of tumor control, normal tissue complication probability in lung cancer patients treated with SBRT using Monte Carlo calculation algorithm.

Purpose/BackgroundWe analyzed the predictive value of non‐x‐ray voxel Monte Carlo (XVMC)‐based modeling of tumor control probability (TCP) and normal tissue complication probability (NTCP) in patients treated with stereotactic body radiotherapy (SBRT) using the XVMC dose calculation algorithm.Materials/MethodsWe conducted an IRB‐approved retrospective analysis in patients with lung tumors treated with XVMC‐based lung SBRT. For TCP, we utilized tumor size‐adjusted biological effective dose (s‐BED) TCP modeling validated in non‐MC dose calculated SBRT to: (1) verify modeling as a function of s‐BED in patients treated with XVMC‐based SBRT; and (2) evaluate the predictive potential of different PTV dosimetric parameters (mean dose, minimum dose, max dose, prescription dose, D95, D98, and D99) for incorporation into the TCP model. Correlation between observed local control and TCPs was assessed by Pearson's correlation coefficient. For NTCP, Lyman NTCP Model was utilized to predict grade 2 pneumonitis and rib fracture.ResultsEighty‐four patients with 109 lung tumors were treated with XVMC‐based SBRT to total doses of 40 to 60 Gy in 3 to 5 fractions. Median follow‐up was 17 months. The 2‐year local and local‐regional control rates were 91% and and 78%, respectievly. All estimated TCPs correlated significantly with 2‐year actuarial local control rates (P < 0.05). Significant corelations between TCPs and tumor control rate according to PTV dosimetric parameters were observed. D99 parameterization demonstrated the most robust correlation between observed and predicted tumor control. The incidences of grade 2 pneumonitis and rib fracture vs. predicted were 1% vs. 3% and 10% vs. 13%, respectively.ConclusionOur TCP results using a XVMC‐based dose calculation algorithm are encouraging and yield validation to previously described TCP models using non‐XVMC dose methods. Furthermore, D99 as potential predictive parameter in the TCP model demonstrated better correlation with clinical outcome.

Physical and Radiobiological Evaluation of Accelerated Intensity Modulated Radiotherapy for Locally Advanced Head and Neck Cancer and Comparison with Short-Term Clinical Outcomes.

Objective:The present study aims to evaluate the accelerated intensity modulated radiotherapy (IMRT) of head and neck (HandN) treatments using physical indices and radiobiological models with its clinical correlation using histogram analysis in radiation therapy (HART). The radiobiological evaluation in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP) indices were compared with acute toxicity. Materials and Methods:A total of twenty patients with stage III and IV of HandN cases treated with accelerated IMRT using 6MV photons were chosen for the study. Using HART software, physical indices of the IMRT plans have been defined by universal plan indices (UPI’s) which summarize the various recognized plan indices. The overall quality factor (QF) of a plan was determined by a linear combination of all indices in UPI set. The clinical outcomes in terms of the acute toxicity like dysphagia and xerostomia were compared with NTCP values of the OAR calculated from HART software. Results:The mean QF and the mean Poisson TCP index was found to be 0.993±0.02 and 0.86 ±0.02 respectively. The mean JT Lyman NTCP index for bilateral parotid, constrictors, and larynx were found to be 0.23±0.14, 0.30±0.17 and 0.22±0.15 respectively. The acute toxicities in terms of severity of xerostomia and dysphagia have shown a moderate correlation with NTCP values of bilateral parotids, constrictors, and larynx, respectively. Conclusion:The mean QF based on UPI was found to be close to unity, which correlates with being a better IMRT plan. The present study suggested the existence of a moderate correlation between the calculated NTCP values and their respective severities of the organ at risk (OAR’s). Accelerated IMRT with chemotherapy is a clinically feasible option in the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) with encouraging initial tumor response and acceptable acute toxicities.

The normal tissue complication probability model-based approach considering uncertainties for the selective use of radiation modality in primary liver cancer patients

PurposeTo predict the probability of radiation-induced liver toxicity (RILT) and implement the normal tissue complication probability (NTCP) model-based approach considering confidence intervals (CIs) to select patients for new treatment techniques, such as proton beam therapy, based on a certain NTCP reduction (ΔNTCP) threshold for primary liver cancer patients. Methods and materialsCommon Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 RILT was scored. The Lyman NTCP models predicting the probability of CTCAE grade ≥2 RILT as a function of the fraction-size adjusted mean liver dose (MLD), using reference fraction size = 2 Gy/fraction and α/β ratio = 2 Gy, were fitted using the maximum likelihood method. At certain combinations of MLDs, ΔNTCP with a CI was evaluated by the delta method. ResultsOf the 239 patients, the incidence of CTCAE grade ≥2 RILT was 55% (46% in the Child–Pugh (CP)-A vs. 81% in the CP-B/C, p < 0.001). Among 180 CP-A patients, 40% who had viral hepatitis infections experienced toxicity vs. 32% in the nonhepatitis subgroup. The MLD was 18 Gy in the toxicity group vs. 16.1 Gy in the nontoxicity group (p = 0.002). The estimated NTCP model parameters specific to the patient subgroups and the ΔNTCP with CI assuming a particular CP classification and viral hepatitis infection status were considerably different which possible changed treatment decision. ConclusionsPatients with CP-A and viral hepatitis infection or CP-B/C cirrhosis had greater susceptibility to CTCAE grade ≥2 RILT. The estimated NTCP and ΔNTCP for individual patients along with a consideration of uncertainties improve the reliability of the NTCP model-based approach.

Radiobiological evaluation of intensity modulated radiation therapy treatments of patients with head and neck cancer: A dual-institutional study.

In clinical practice, evaluation of clinical efficacy of treatment planning stems from the radiation oncologist's experience in accurately targeting tumors, while keeping minimal toxicity to various organs at risk (OAR) involved. A more objective, quantitative method may be raised by using radiobiological models. The purpose of this work is to evaluate the potential correlation of OAR-related toxicities to its radiobiologically estimated parameters in simultaneously integrated boost (SIB) intensity modulated radiation therapy (IMRT) plans of patients with head and neck tumors at two institutions. Lyman model for normal tissue complication probability (NTCP) and the Poisson model for tumor control probability (TCP) models were used in the Histogram Analysis in Radiation Therapy (HART) analysis. In this study, 33 patients with oropharyngeal primaries in the head and neck region were used to establish the correlation between NTCP values of (a) bilateral parotids with clinically observed rates of xerostomia, (b) esophagus with dysphagia, and (c) larynx with dysphagia. The results of the study indicated a strong correlation between the severity of xerostomia and dysphagia with Lyman NTCP of bilateral parotids and esophagus, respectively, but not with the larynx. In patients without complications, NTCP values of these organs were negligible. Using appropriate radiobiological models, the presence of a moderate to strong correlation between the severities of complications with NTCP of selected OARs suggested that the clinical outcome could be estimated prior to treatment.

Is There a Dose Response Relationship for Pulmonary Function Changes After Stereotactic Body Radiation Therapy for Early-stage Non-small Cell Lung Cancer?

Is There a Dose Response Relationship for Pulmonary Function Changes After Stereotactic Body Radiation Therapy for Early-stage Non-small Cell Lung Cancer?

Dosimetric Analysis of Radiation-induced Gastric Bleeding

Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of ≥grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD₅₀ (normal) = 56 Gy and TD₅₀ (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD₅₀ value for the cirrhosis patients points out their greater sensitivity. This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.

Risk of breast fibrosis following irradiation using a breast-specific SBRT system compared with conventional APBI.

116 Background: To determine the dosimetric characteristics and risk of breast fibrosis using a normal tissue complication probability (NTCP) model in conjunction with a novel preoperative stereotactic radiotherapy system called the GammaPod. Results are compared with linac based post-lumpectomy APBI plans for the same cohort. Methods: The GammaPod breast SBRT system consists of a Co-60 irradiation unit in combination with an immobilization device with embedded fiducials. Eight patients were enrolled in an IRB-approved protocol and underwent CT scans in the prone position with breast immobilization. A preoperative target (GTV) was synthesized to match the tumor location and volume reported in imaging studies obtained prior to surgery (0.3-2.4 cc). The GTV was expanded by 1.5 cm to create a CTV, and a PTV was created using an additional 0.3 cm margin. The PTV was prescribed 25.5 Gy in 3 fx, which is radiobiologically equivalent to conventional APBI doses of 38.5 Gy in 10 fx. Following the radioablative experience in NSCLC, we also planned to deliver 60.0 Gy to the GTV+0.3 cm as a simultaneous boost in conjunction with the 25.5 Gy PTV prescription dose. For comparison, linac-based treatment plans were created for the same cohort following NSABP B-39 guidelines. Whole breast dosimetry was analyzed in terms of biologically equivalent dose (BED) and Lyman NTCP analysis was performed. Results: The volume of ipsilateral breast receiving 10, 20, 50, and 100% of the prescribed dose was substantially smaller in GammaPod vs. APBI plans, with cohort averages of 19.3, 13.0, 7.1 and 4.0% vs. 75.8, 67.3, 48.1 and 27.6% respectively (p&lt;0.001). Even though the PTV equivalent uniform BED (EUD) was substantially higher in GammaPod plans (87.9 Gy vs. 57.3 Gy), the ipsilateral breast EUD was still smaller in these plans, 18.9 ± 5.0 Gy vs. 47.2 ± 3.2 Gy (p&lt;0.001). Corresponding NTCP predictions for breast fibrosis rates following GammaPod and APBI treatments were 0.2 ± 0.1% vs. 2.8 ± 0.8% (p&lt;0.001), respectively. Conclusions: The GammaPod system improves upon traditional post-lumpectomy linac-based APBI by decreasing dose to the ipsilateral breast as well as the predicted rates of breast fibrosis.

Analysis of acute radiation-induced esophagitis in non-small-cell lung cancer patients using the Lyman NTCP model

Purpose To analyze acute esophagitis (AE) in a Chinese population receiving 3D conformal radiotherapy (3DCRT) for non-small cell lung cancer (NSCLC), combined or not with chemotherapy (CT), using the Lyman–Kutcher–Burman (LKB) normal tissue complication probability (NTCP) model. Materials and methods 157 Chinese patients (pts) presented with NSCLC received 3DCRT: alone (34 pts) or combined with sequential CT (59 pts) (group 1) or with concomitant CT (64 pts) (group 2). Parameters (TD 50, n, and m) of the LKB NTCP model predicting for > grade 2 AE (RTOG grading) were identified using maximum likelihood analysis. Univariate and multivariate analyses using a binary regression logistic model were performed to identify patient, tumor and dosimetric predictors of AE. Results Grade 2 or 3 AE occurred in 24% and 52% of pts in group 1 and 2, respectively ( p < 0.001). For the 93 group 1 pts, the fitted LKB model parameters were: m = 0.15, n = 0.29 and TD 50 = 46 Gy. For the 64 group 2 pts, the parameters were: m = 0.42, n = 0.09 and TD 50 = 36 Gy. In multivariate analysis, the only significant predictors of AE were: NTCP ( p < 0.001) and V 50, as continuous variable (RR = 1.03, p = 0.03) or being more than a threshold value of 11% (RR = 3.6, p = 0.009). Conclusions A LKB NTCP model has been established to predict AE in a Chinese population, receiving thoracic RT, alone or combined with CT. The parameters of the models appear slightly different than the previous one described in Western countries, with a lower volume effect for Chinese patients.

Late Rectal Toxicity on RTOG 94-06: Analysis Using a Mixture Lyman Model

To estimate the parameters of the Lyman normal-tissue complication probability model using censored time-to-event data for Grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for three-dimensional conformal radiotherapy of prostate cancer. The Lyman normal-tissue complication probability model was fitted to data from 1,010 of the 1,084 patients accrued on Radiation Therapy Oncology Group 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose-volume histograms for whole rectum and dose-wall histograms for rectal wall. With a median follow-up of 7.2 years, the crude incidence of Grade ≥2 late rectal toxicity was 15% (n = 148). The parameters of the Lyman model fitted to dose-volume histograms data, with 95% profile-likelihood confidence intervals, were TD(50) = 79.1 Gy (75.3 Gy, 84.3 Gy), m = 0.146 (0.107, 0.225), and n = 0.077 (0.041, 0.156). The fit based on dose-wall histogram data was not significantly different. Patients with cardiovascular disease had a significantly higher incidence of late rectal toxicity (p = 0.015), corresponding to a dose-modifying factor of 5.3%. No significant association with late rectal toxicity was found for diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, or prescribed dose per fraction (1.8 Gy vs. 2 Gy). These results, based on a large cohort of patients from a multi-institutional trial, are expected to be widely representative of the ability of the Lyman model to describe the long-term risk of Grade ≥2 late rectal toxicity after three-dimensional conformal radiotherapy of prostate cancer.

A Dosimetric Model of Duodenal Toxicity After Stereotactic Body Radiotherapy for Pancreatic Cancer

Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT. Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V(5) (volume of duodenum that received 5 Gy), V(10), V(15), V(20), V(25), and D(max) (maximum dose to 1 cm(3)). Normal tissue complication probability (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models. The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V(10)-V(25) and D(max) all correlated significantly with duodenal toxicity (p<0.05). In particular, V(15)≥9.1 cm(3) and V(15)<9.1 cm(3) yielded duodenal toxicity rates of 52% and 11%, respectively (p=0.002); V(20)≥3.3 cm(3) and V(20)<3.3 cm(3) gave toxicity rates of 52% and 11%, respectively (p=0.002); and D(max)≥23 Gy and D(max)<23 Gy gave toxicity rates of 49% and 12%, respectively (p=0.004). Lyman NTCP model optimization generated the coefficients m=0.23, n=0.12, and TD(50)=24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p=0.001). Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies.

Impact of Toxicity Grade and Scoring System on the Relationship Between Mean Lung Dose and Risk of Radiation Pneumonitis in a Large Cohort of Patients With Non–Small Cell Lung Cancer

To compute the risk of radiation pneumonitis (RP) as a function of mean lung dose (MLD), with RP scored using three grading systems and analyzed at four threshold levels of toxicity in a large cohort of patients with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy (RT). On the basis of medical records and radiographic images, RP was scored retrospectively in 442 patients with NSCLC who had >or=6 months of follow-up after the end of RT. The severity of RP was scored for each patient using the National Cancer Institute (NCI) Common Toxicity Criteria, version 2.0 (CTC2.0); the NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE3.0); and the grading system of the Radiation Therapy Oncology Group (RTOG). For each grading system and for each of four levels of toxicity (Grade >or=1, >or=2, >or=3, >or=4), the Lyman, logistic, and log-logistic normal tissue complication probability (NTCP) models were fitted to the data as functions of MLD. The parameter estimates from the model fits are listed in table form, and the RP risk estimates are presented graphically for the Lyman and log-logistic NTCP models. The results presented here illustrate the impact of scoring system and level of toxicity on the relationship between MLD and RP risk. These results facilitate quantitative comparisons between our data and studies of RP risk reported by others, and several examples of such comparisons are provided.

Duodenal Toxicity in Single-fraction Stereotactic Body Radiotherapy

Dose escalation for pancreas cancer is limited by the tolerance of the duodenum, especially with stereotactic body radiotherapy (SBRT). This study reports on the dosimetric determinants of duodenal toxicity with single-fraction radiotherapy. Fifty-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Common Terminology Criteria for Adverse Events v3 (CTCAE) was used to score all duodenal toxicity. Dose–volume histogram (DVH) endpoints evaluated include V5 (volume of duodenum in cm3 that received 5 Gy), V10, V15, V20, V25, and Dmax (maximum dose to 1 cm3). Normal tissue complication probability (NTCP) was evaluated with a Lyman model through estimation of the parameters m, n, and TD50 using the log-likelihood method. Univariate and multivariate analysis was conducted with Kaplan-Meier and Cox-regression models, respectively. Ten patients (19%) experienced Grade 2–4 duodenal toxicity. The median time to toxicity was 6.6 months (range, 1.6–10.5 months). The 6- and 12-month actuarial rates of duodenal toxicity were 12% and 32%, respectively. The V10 - V25, and Dmax all correlated significantly with duodenal toxicity (p < 0.05). In particular, V15 ≥13 cm3 and V15 <13 cm3 yielded 1-year duodenal toxicity rates of 64% and 6.2%, respectively, (p = 0.001); V20 ≥6.6 cm3, and V20 <6.6 cm3 gave toxicity rates of 61% and 4.8%, respectively, (p = 0.004); and Dmax ≥24.6 Gy and Dmax <24.6 Gy gave toxicity rates of 73% and 4.8%, respectively, (p = 0.001). Lyman NTCP model optimization generated the coefficients m = 0.15, n = 5.1, and TD50 = 22.5 Gy. Gender, age, tumor location, palliative bypass surgery, presence of a biliary stent, and chemotherapy did not correlate with toxicity on univariate analysis. Only the Lyman NTCP model remained significant in multivariate analysis (p = 0.028). Multiple DVH endpoints, as well as a Lyman NTCP model, are strongly predictive of duodenal toxicity. These dose constraints will be valuable in future studies with abdominal SBRT.

The significance of the choice of Radiobiological (NTCP) models in treatment plan objective functions

A Clinician's discrimination between radiation therapy treatment plans is traditionally a subjective process, based on experience and existing protocols. A more objective and quantitative approach to distinguish between treatment plans is to use radiobiological or dosimetric objective functions, based on radiobiological or dosimetric models. The efficacy of models is not well understood, nor is the correlation of the rank of plans resulting from the use of models compared to the traditional subjective approach. One such radiobiological model is the Normal Tissue Complication Probability (NTCP). Dosimetric models or indicators are more accepted in clinical practice. In this study, three radiobiological models, Lyman NTCP, critical volume NTCP and relative seriality NTCP, and three dosimetric models, Mean Lung Dose (MLD) and the Lung volumes irradiated at 10Gy (V10) and 20Gy (V20), were used to rank a series of treatment plans using, harm to normal (Lung) tissue as the objective criterion. None of the models considered in this study showed consistent correlation with the Radiation Oncologists plan ranking. If radiobiological or dosimetric models are to be used in objective functions for lung treatments, based on this study it is recommended that the Lyman NTCP model be used because it will provide most consistency with traditional clinician ranking.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10 cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. There are five parameters in the model: TD(50), m, n, alpha/beta and f. With two parameters n and alpha/beta fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD(50)(1) = 40.3 +/- 8.4Gy, m =0.36 +/- 0.09, f = 0.156 +/- 0.074 Gy and TD(50)(1) = 23.9 +/- 5.3Gy, m = 0.41 +/- 0.15, f = 0.0 +/- 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.

Analysis of Radiation Pneumonitis Risk Using a Generalized Lyman Model

To introduce a version of the Lyman normal-tissue complication probability (NTCP) model adapted to incorporate censored time-to-toxicity data and clinical risk factors and to apply the generalized model to analysis of radiation pneumonitis (RP) risk. Medical records and radiation treatment plans were reviewed retrospectively for 576 patients with non-small cell lung cancer treated with radiotherapy. The time to severe (Grade >/=3) RP was computed, with event times censored at last follow-up for patients not experiencing this endpoint. The censored time-to-toxicity data were analyzed using the standard and generalized Lyman models with patient smoking status taken into account. The generalized Lyman model with patient smoking status taken into account produced NTCP estimates up to 27 percentage points different from the model based on dose-volume factors alone. The generalized model also predicted that 8% of the expected cases of severe RP were unobserved because of censoring. The estimated volume parameter for lung was not significantly different from n = 1, corresponding to mean lung dose. NTCP models historically have been based solely on dose-volume effects and binary (yes/no) toxicity data. Our results demonstrate that inclusion of nondosimetric risk factors and censored time-to-event data can markedly affect outcome predictions made using NTCP models.

Fit of a Generalized Lyman Normal-Tissue Complication Probability (NTCP) Model to Grade ≥ 2 Late Rectal Toxicity Data From Patients Treated on Protocol RTOG 94-06

RTOG 94-06 was a multi-institutional dose-escalation trial designed to determine the maximum tolerated dose for 3D conformal radiotherapy (3D-CRT) of prostate cancer. The purpose of the present study was to estimate the parameters of the Lyman NTCP model using censored time-to-toxicity data for the grade ≥ 2 rectal toxicity endpoint among patients treated on RTOG 94-06.