Dose-volume Factors Research Articles

Thyroid Dysfunction Following Supraclavicular Irradiation in The Management of Carcinoma of the Breast.

Radiation induced thyroid dysfunction is usually underestimated in patients with breast cancer who had supraclavicular irradiation (RT). In the present study, a total of 28 patients with breast cancer received supraclavicular RT were evaluated focusing on radiation dose-volume factors in relation to thyroid function. Thyroid function tests, including serum thyroid stimulating hormone, free thyroxine, free triiodothyronine, were analyzed prior to RT and 3, 6, 9, 12, 18 and 24 months after RT. Based on each patient’s dose volume histogram (DVH), total volume of the thyroid, mean radiation dose the thyroid and percentages of thyroid volume which received radiation doses 10-50 Gy (V10-V50) were considered for statistical analysis. The median follow-up time was 25 months (range, 12.3-36 months). Of 28 patients 6 (21%) were diagnosed with hypothyroidism (HT). The median time to the development of HT was 9 months (range: 3-18 months). Mean thyroid dose was 31 Gy (19-48 Gy) and mean thyroid volume was 32 cc (12-64 cc). We found that V20 (OR= 10, 95% CI= 1.15-86.88, p= 0.05), V30 (OR= 10, 95% CI= 1.15-86.88, p= 0.05) and V40 (OR= 21, 95% CI= 1.61-273.34, p= 0.02) and mean thyroid dose ≥36 Gy (OR= 10, 95% CI= 1.15-86.88) (p= 0.05), had a significant impact on development of HT. Moreover, significant elevation was observed in mean TSH level between baseline (1.85±1.47 mIU/L) and at 6 months (3.80±7.42 mIU/L), (p= 0.003). Supraclavicular RT in patients with breast cancer appear to amplify the risk of HT. We believe further investigations in larger cohort are required to confirm our results.

Radiation pneumonitis after stereotactic radiation therapy for lung cancer.

Stereotactic body radiation therapy (SBRT) has a local control rate of 95% at 2 years for non-small cell lung cancer (NSCLC) and should improve the prognosis of inoperable patients, elderly patients, and patients with significant comorbidities who have early-stage NSCLC. The safety of SBRT is being confirmed in international, multi-institutional Phase II trials for peripheral lung cancer in both inoperable and operable patients, but reports so far have found that SBRT is a safe and effective treatment for early-stage NSCLC and early metastatic lung cancer. Radiation pneumonitis (RP) is one of the most common toxicities of SBRT. Although most post-treatment RP is Grade 1 or 2 and either asymptomatic or manageable, a few cases are severe, symptomatic, and there is a risk for mortality. The reported rates of symptomatic RP after SBRT range from 9% to 28%. Being able to predict the risk of RP after SBRT is extremely useful in treatment planning. A dose-effect relationship has been demonstrated, but suggested dose-volume factors like mean lung dose, lung V20, and/or lung V2.5 differed among the reports. We found that patients who present with an interstitial pneumonitis shadow on computed tomography scan and high levels of serum Krebs von den Lungen-6 and surfactant protein D have a high rate of severe radiation pneumonitis after SBRT. At our institution, lung cancer patients with these risk factors have not received SBRT since 2006, and our rate of severe RP after SBRT has decreased significantly since then.

Variation of PTV dose distribution on patient size in prostate VMAT and IMRT: a dosimetric evaluation using the PTV dose–volume factor

AbstractBackgroundWe propose to use the PTV dose–volume factor (PDVF) to evaluate treatment plans of prostate volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT).PurposePDVF was used to compare the variation of planning target volume (PTV) coverage between VMAT and IMRT because of weight loss of patient.Materials and methodsVMAT and IMRT plans of five patients (prostate volume = 32–86·5 cm3) using the 6 MV photon beams were created with the external contour reduced by depths of 0·5–2 cm to reflect the weight loss. Moreover, integral doses (volume integral of the patient dose) and prostate tumour control probability (TCP) were calculated.ResultsWe found that reduced depth resulted in PDVF decreasing 0·03 ± 4·7 × 10−4 (VMAT) and 0·04 ± 9·7 × 10−3 (IMRT) per cm for patients. The decrease of PDVF or degradation of PTV coverage was found more significant in IMRT plans than VMAT with patient size reduction. The integral dose did not change significantly between VMAT and IMRT, while the prostate TCP increased with an increase of reduced depth.ConclusionWe concluded that PDVF can be successfully used to evaluate the variation of PTV coverage because of weight loss of patient in prostate VMAT and IMRT. Degradation of PTV coverage in prostate VMAT is less significant than IMRT regarding patient size reduction.

Preoperative chemoradiotherapy for pancreatic cancer encountered vertebral compression fractures.

227 Background: Preoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer at our institute achieved excellent cure rates, while treated patients encountered vertebral compression fractures (VCFs) frequently. Methods: From January 2006 to December 2011, 220 patients (male/female: 134/86, median age: 66 (range: 33-84)) with resectable pancreatic cancer have been treated with preoperative CRT with GEM. This method consisted of concurrent radiotherapy (50-60 Gy in 25 fractions over 5 weeks) and chemotherapy (GEM 1,000 mg/m2intravenous, weekly for 12-15 weeks, 3 times during 4 weeks). Three-dimensional conformal radiotherapy was used and its fields covered both primary pancreatic tumor and retropancreatic tissues with 50 Gy level. Boost irradiation to the roots of celiac and superior mesenteric arteries with 2.4 Gy/fr using field-within-field technique has been started since 2009. The risk factors for VCF and its causes were retrospectively analyzed for 1,308 Th10-L3 vertebral bodies. Results: Follow-up time from the initiation of CRT ranged from 3.4-73.9 months (median: 17.9). Median overall survival time of these patients was 40.6 months. Radical surgery was completed in 164 patients (75%). Twenty-five patients (11%) diagnosed as VCF (CTCAE v4.0 grade1/2: 12/13) and 22 of them were at 3.6-23 months from CRT. Cumulative incidence rates at 2 years were 18.9% in total, 8.5% in male and 38.4% in female (p = 0.0002). Corresponding rates were 5.1% in age < 60 and 24.9% in age ≥ 60 (p = 0.0107). On their courses 37 de novo VCFs (Th10/11/12/L1/2/3: 2/3/11/13/7/1) were observed at first and 9 patients repeated VCFs near the initial VCFs. Dose-volume factors of each vertebral bodies also significantly correlated with VCF; vertebrae whose mean dose were < 38 Gy/ ≥ 38 Gy developed VCFs in 2.7%/10.0% at 2 years (p < 0.0001), vertebrae whose V30 were < 80%/≥80% developed VCFs in 2.4%/10.6% (p < 0.0001). Conclusions: Besides women and higher age, dose-volume factors of radiotherapy were risk of developing VCF in patients with pancreatic cancer after preoperative CRT with GEM. These findings should be considered to avoid VCFs as late adverse event after CRT for pancreatic cancer, especially in IMRT era.

1636 - A Prospective Study of Subacute Thyroid Dysfunction Following Supraclavicular Irradiation in the Management of Carcinoma of the Breast

ABSTRACT Purpose To evaluate the relationship between irradiation and early thyroid dysfunction, focusing on radiation dose-volume factors. Patients and methods Between December 2010 and January 2012 a total of 21 patients with breast cancer received supraclavicular irradiation were evaluated Thyroid function tests, including serum thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), were analyzed prior to irradiation and every three months the first year and then 18th month after radiotherapy. Based on each patient's dose volume histogram (DVH), total volume of the thyroid, mean radiation dose the thyroid and percentages of thyroid volume which received radiation doses 10-60Gy (V10-V60) were considered for statistical analysis. Results Mean TSH levels before irradiation, at 3, 6, 9 and 12 months were 1.4 µIU/ml, 1.5 µIU/ml, 1.7 µIU/ml, 3.6 µIU/ml and 4.6 µIU/ml, respectively. Serum TSH levels did not change significantly at 3 and 6 months after irradiation (p = 0.1). However, a significant elevation was noted at 9 months (p = 0.005). Mean thyroid dose was 32 Gy (19-48 Gy) and mean thyroid volume was 35 cc (24-64 cc). Median values of V10-20-30-40-50-60 were 68%, 58%, 55%, 53%, 48% and 0%, respectively. With a median follow-up was 9 months (range, 3-18 months), only one patient (5%) developed clinical hypothyroidism requiring thyroid replacement treatment. Conclusion According to early results of our study, irradiation of the thyroid develops early thyroid dysfunction. This damage is initially manifested within 9 months after radiotherapy. However we could not analyze the radiation dose-volume factors of the peak level of serum TSH because of inefficient follow up time. Disclosure All authors have declared no conflicts of interest.

Poster - Thur Eve - 59: Dosimetric evaluation on the variation of PTV coverage due to patient size reduction using the prostate dose-volume factor in prostate radiotherapy.

We proposed to use the prostate dose-volume factor (PDVF), derived from the dose-volume dataset of planning target volume (PTV) in prostate radiotherapy to evaluate treatment plans of prostate volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT). To demonstrate plan evaluation using PDVF, VMAT and 7-beam IMRT plans were created in three patients with prostate volumes equal to 32, 48.4 and 86.5 cm3 . Dose variation of PTV was made by reducing the body contour of the patients with reduced depth equal to 0.5 - 2 cm, mimicking a patient size reduction in the treatment. The Gaussian error function was used to model the cumulative dose-volume histogram of the PTV, and PDVF was calculated as per the parameters of the error function. PDVF = 1 reflects an ideal PTV coverage (i.e. 100% prescribed dose in 100% target volume). We found that for PDVF ranged 0.98 - 1 in prostate VMAT and IMRT without patient size change, reduced depth led to PDVF decreasing 0.03 ± 4.7 × 10-4 (VMAT) and 0.04 ± 9.7 × 10-3 (IMRT) per cm for the patients. The variation of PTV coverage on the prostate volume due to the reduced depth was less significant in VMAT plans than IMRT. It is concluded that PDVF was successfully used to evaluate the variation of PTV coverage due to the weight loss of patient in prostate VMAT and IMRT. Degradation of PTV coverage in prostate VMAT regarding patient size reduction is less significant than that in IMRT.

Esophageal Toxicity From High-Dose, Single-Fraction Paraspinal Stereotactic Radiosurgery

To report the esophageal toxicity from single-fraction paraspinal stereotactic radiosurgery (SRS) and identify dosimetric and clinical risk factors for toxicity. A total of 204 spinal metastases abutting the esophagus (182 patients) were treated with high-dose single-fraction SRS during 2003-2010. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Dose-volume histograms were combined to generate a comprehensive atlas of complication incidence that identifies risk factors for toxicity. Correlation of dose-volume factors with esophageal toxicity was assessed using Fisher's exact test and logistic regression. Clinical factors were correlated with toxicity. The median dose to the planning treatment volume was 24 Gy. Median follow-up was 12 months (range, 3-81). There were 31 (15%) acute and 24 (12%) late esophageal toxicities. The rate of grade ≥3 acute or late toxicity was 6.8% (14 patients). Fisher's exact test resulted in significant median splits for grade ≥3 toxicity at V12 = 3.78 cm(3) (relative risk [RR] 3.7, P=.05), V15 = 1.87 cm(3) (RR 13, P=.0013), V20 = 0.11 cm(3) (RR 6, P=0.01), and V22 = 0.0 cm(3) (RR 13, P=.0013). The median split for D2.5 cm(3) (14.02 Gy) was also a significant predictor of toxicity (RR 6; P=.01). A highly significant logistic regression model was generated on the basis of D2.5 cm(3). One hundred percent (n = 7) of grade ≥4 toxicities were associated with radiation recall reactions after doxorubicin or gemcitabine chemotherapy or iatrogenic manipulation of the irradiated esophagus. High-dose, single-fraction paraspinal SRS has a low rate of grade ≥3 esophageal toxicity. Severe esophageal toxicity is minimized with careful attention to esophageal doses during treatment planning. Iatrogenic manipulation of the irradiated esophagus and systemic agents classically associated with radiation recall reactions are associated with development of grade ≥4 toxicity.

Dose–Volume Metrics Associated With Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Lung Cancer

To identify dose-volume factors associated with radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for lung cancer. This study analyzed 74 patients who underwent SBRT for primary lung cancer. The prescribed dose for SBRT was uniformly 48 Gy in four fractions at the isocenter. RP was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.3. Symptomatic RP was defined as grade 2 or worse. Optimal cut-offs dividing the patient population into two subgroups based on the incidence of symptomatic RP were sought using the following dose-volume metrics: PTV volume (ml), mean lung dose (Gy), and V5, V10, V15, V20, V25, V30, V35, and V40 (%) of both lungs excluding the PTV. With a median follow-up duration of 31.4 months, symptomatic RP was observed in 15 patients (20.3%), including 1 patient with grade 3. Optimal cut-offs for pulmonary dose-volume metrics were V25 and V20. These two factors were highly correlated with each other, and V25 was more significant. Symptomatic RP was observed in 14.8% of the patients with V25 <4.2%, and the rate was 46.2% in the remainder (p = 0.019). PTV volume was another significant factor. The symptomatic RP rate was significantly lower in the group with PTV <37.7 ml compared with the larger PTV group (11.1% vs. 34.5%, p = 0.020). The patients were divided into three subgroups (patients with PTV <37.7 ml; patients with, PTV ≥37.7 ml and V25 <4.2%; and patients with PTV ≥37.7 ml and V25 ≥4.2%); the incidence of RP grade 2 or worse was 11.1%, 23.5%, and 50.0%, respectively (p = 0.013). Lung V25 and PTV volume were significant factors associated with RP after SBRT.

Dose-Volume Factors to Select Patient-Specific Image-Guidance Action Thresholds in Prostate Cancer

For radiation delivery tracking systems that monitor intrafraction prostate motion, generalized departmental threshold protocols may be used. The purpose of this study is to determine whether predefined action thresholds can be generally applied or if patient-specific action thresholds may be required. Software algorithms were developed in the MatLab (The Mathworks Inc., Natick, MA) software environment to simulate shifts of the patient structure set consisting of prostate, bladder, and rectum. These structures were shifted by 1/2 10 mm in each direction in 1 mm increments to simulate displacements during treatment, without taking into consideration organ deformity. Dose-volume data at each shift were plotted and analyzed. A linear relationship was observed between planning dose-volume parameters and shifted dose-volume parameters. For a 5 mm anterior shift, it was observed that individual rectal V70 values increased by absolute magnitudes of 6-15%, dependent on the planning rectal V70 of each patient. Likewise, for a 5 mm inferior shift, individual bladder V70 values increased by 1-14%, dependent on planning bladder V70. This linear relationship was observed for all levels of shifts up to 10 mm. Since rectum and bladder dose-volume changes due to patient shifts are dependent on dose-volume parameters, this study suggests that patient-specific action thresholds may be necessary.

Analysis of Dose-Volume Metrics Associated with Radiation Pneumonitis after Stereotactic Body Radiotherapy for Lung Cancer

The objective was to find dose-volume factors associated with radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) for lung cancer. Seventy-four patients who underwent SBRT for primary lung cancer were analyzed in the present study. Fifty-five were male, and nineteen were female. A median of age was 77 years old (range, 63-88). Chemotherapy was not administered unless disease progression was confirmed. Prescription dose for SBRT was uniformly 48 Gy in 4 fractions at the isocenter. Irradiation was performed with 6-MV X-ray beams, which were shaped into the planning target volume (PTV) plus 5-mm margins, from a linear accelerator (Clinac 2300 C/D; Varian). Dose distribution was re-calculated with the analytical anisotropic algorithm in Eclipse (Varian). RP was graded according to the CTCAE version 3, and high-grade RP was herein defined as Grade 2 or worse. Optimal cut points dividing the patient population into two subgroups based on incidence of high-grade RP were searched using the recursive partitioning method in the following dose-volume metrics: PTV volume (cc), mean lung dose (Gy), V5, V10, V15, V20, V25, V30, V35, and V40, where Vd was defined as a relative volume (%) of the lung other than PTV which received more than a threshold dose d Gy. RP Grade 2 or worse was observed in 15 patients (20.2%), including 1 patient of Grade 3, with a median follow-up duration of 31 months. Optimal cut points for pulmonary doses were found in V25 and V20. These factors were highly correlated with each other (R = 0.99), and V25 was more significant than V20. High-grade RP rate was 14.8% in the patients with V25 less than 4.2%, while the rate was 46.2% in the remainder (p = 0.02). PTV volume was found as the other significant factor. High-grade RP rate was significantly lower in the group with PTV volume less than 37.7 cc compared with the larger PTV group (11.1% vs. 34.5%, p = 0.02). Correlation between lung V25 and PTV volume was not strong (R = 0.58). When dividing the patient population into three subgroups: (1) PTV < 37.7 cc; (2) PTV ≥ 37.7 cc and V25 < 4.2%; and (3) PTV ≥ 37.7 cc and V25 ≥ 4.2%, incidence rates of high-grade RP were 11.1%, 23.5%, and 50.0%, respectively (p = 0.01). Lung V25 and PTV volume were suggested as significant factors associated with RP after SBRT.

Improving Normal Tissue Complication Probability Models: The Need to Adopt a “Data-Pooling” Culture

Clinical studies of the dependence of normal tissue response on dose-volume factors are often confusingly inconsistent, as the QUANTEC reviews demonstrate. A key opportunity to accelerate progress is to begin storing high-quality datasets in repositories. Using available technology, multiple repositories could be conveniently queried, without divulging protected health information, to identify relevant sources of data for further analysis. After obtaining institutional approvals, data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors (whether dosimetric, image-based, clinical, socioeconomic, or biological). Data pooling has already been carried out effectively in a few normal tissue complication probability studies and should become a common strategy.

Radiation Pneumonitis Following Twice-daily Radiotherapy with Concurrent Carboplatin and Paclitaxel in Patients with Stage III Non-small-cell Lung Cancer

To examine the effects of dose-volume factors on the development of radiation pneumonitis in patients with non-small-cell lung cancer who received twice-daily radiotherapy concurrently with carboplatin and paclitaxel chemotherapy. Radiotherapy consisted of twice-daily fractionation of 1.2 Gy, to a total dose of 60 Gy. Weekly carboplatin and paclitaxel were used as a concurrent chemotherapy. Effects of radiotherapy parameters on the development of radiation pneumonitis were retrospectively analyzed. Fourteen of 37 patients developed Grade 2 or worse (> or = G2) radiation pneumonitis. Grade 2 or worse radiation pneumonitis occurred in all 5 patients with V5 >40%, all 4 patients with V10 >35%, all 4 patients with V13 >32%, 9 of 14 patients with V20 >24% and 8 of 11 patients with V30 >22%, whereas 9 of 32 patients with V5 <40%, 10 of 33 patients with V10 <35%, 10 of 33 patients with V13 <32%, 5 of 23 patients with V20 <24% and 6 of 26 patients with V30 <22%, with respective P values of 0.0045, 0.015, 0.015, 0.015 and 0.008. Eight of 11 patients with a mean lung dose of >14 Gy developed > or = G2 radiation pneumonitis in contrast to 6 of 26 patients with a mean lung dose of <14 Gy (P = 0.008). Several cut-off values in the V(dose) and the mean lung dose differentiating probabilities of developing > or = G2 radiation pneumonitis were identified in this combination therapy.

Dosimetric analysis for thyroid disorders after radiotherapy to the neck

e17025 Background: In our study, we aimed to evaluate the possible predictors of thyroid disorders after radiotherapy to the neck, focusing on radiation dose-volume factors. Methods: Thyroid function was measured in 65 patients treated with radiation ports including the thyroid, between 2005 and 2008. All of the radiation-induced thyroid dysfunction was determined with an endpoint of abnormal thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and thyroxine (fT4), thyroglobulin antibodies (ATG), thyroid peroxidase antibodies (TPA), thyroid binding globulin (TBG) levels. In 65 patients, radiation dose-volume parameters were calculated; e.g. total volume of the thyroid, mean radiation dose to the thyroid, and percentage of the thyroid volume which received radiation doses of no less than 10–50 Gy (V10-V50). The evaluated risk factors for thyroid dysfunction included these dose-volume parameters, sex, age, treatment modality and primary disease. Results: Most patients (72.3%) had a normal thyroid function, 17 (26.2%) hypothyroidism, 1 (1.5%) hyperthyroidism, and 12 (18.4%) thyroiditis with normal thyroid function. Four of 17 patients with hypothyroidism had overt hypothyroidism. In our analysis, DVHs (dose volume histograms) were calculated and no associations were found between the V10, V20, V40, and V50 percentages and thyroid disorders. V30 and minimum absorbed thyroid dose (Dmin) more than 25 Gy appeared to be correlated with high TSH values (p = 0.01 and p = 0.04, respectively). The patients with hypothyroidism were between 40–60 years. Female gender was associated with a higher incidence of TBG abnormality. Baseline TSH values were available in 16 patients, and hypothyroidism was diagnosed in 4 (25%) of them. No correlation was found between tumor-related variables and incidence of thyroid disorders. Conclusions: Thyroid disorders after radiation therapy to the neck still represent a clinically underestimated problem. Further prospective well designed studies on dose-effect relationship for radiotherapy-induced thyroid toxicity are therefore needed, and thyroid should be considered as an organ at risk in all patients treated for head and neck tumors. No significant financial relationships to disclose.

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.

Dose-volume Histogram Parameters and Clinical Factors Associated with Pleural Effusion in Esophageal Cancer Patients after Treated with Chemoradiotherapy

Dose-volume Histogram Parameters and Clinical Factors Associated with Pleural Effusion in Esophageal Cancer Patients after Treated with Chemoradiotherapy

Lung Perfusion Score Can Predict Future Pulmonary Complications After Radiation Therapy in Patients With Lung Cancer

17% to 24%) and 23% (95% C.I. 19% to 27%), respectively. In univariate analyses, smoking status (150 current smokers, 371 previous smokers, and 46 nonsmokers, p\0.001), nodal status (104 node negative, 363 node positive, p = 0.029), volume of normal lung (median 3486 cc, range 1252 to 7870 cc, p = 0.003), percent of total lung represented by the GTV (median 3.5%, range \0.1% to 37.5%, p = 0.010), use of 4D-CT (N = 122, p = 0.048) and IMRT (N = 84, p = 0.034), mean dose to (normal) lung (median 21.1 Gy, range 2.1 Gy to 40.1 Gy, p 0.001), relative volumes of normal lung rV5 to rV65, in increments of 5 Gy were associated with TRP with statistical significance by univariate analyses. In multivariate analyses (MV), higher rV30 (p 0.001), nonsmoker (p = 0.001), and former smoker (p = 0.030) were the only 3 independent factors with increased risk of TRP. Each of the factors significant by univariate, analysis but not by MV analysis, is significantly associated (Mann-Whitney test) with differences in rV30. Further analysis demonstrated that the majority of non-smokers were healthy women who had smaller lung volume with adenocarcinoma, who received induction chemotherapy, and had higher mean V30-45, compared with smokers. Conclusions: The only clinical factor other than dose-volume factors that significantly impacts TRP risk is smoking status. Many different dose-volume factors were significantly associated with differences in time to TRP. Additional analysis is needed to identify what dose range of lung radiation is most important biologically. Based on the fits of the MV models, we can identify patient subgroups with markedly different risk, but we have not yet identified a high-risk group with an expected incidence of .50%. Therefore, there are undoubtedly other risk factors yet to be identified.

Predicting Treatment Outcomes using a Genetic Algorithm

To develop a genetic algorithm for the variable selection in logistic regression for the statistical analysis of radiotherapy outcome based on physiological, biological, clinical and dose-volume factors.

Investigation of the support vector machine algorithm to predict lung radiation‐induced pneumonitis

The purpose of this study is to build and test a support vector machine (SVM) model to predict for the occurrence of lung radiation-induced Grade 2+ pneumonitis. SVM is a sophisticated statistical technique capable of separating the two categories of patients (with/without pneumonitis) using a boundary defined by a complex hypersurface. Despite the complexity, the SVM boundary is only minimally influenced by outliers that are difficult to separate. By contrast, the simple hyperplane boundary computed by the more commonly used and related linear discriminant analysis method is heavily influenced by outliers. Two SVM models were built using data from 219 patients with lung cancer treated using radiotherapy (34 diagnosed with pneumonitis). One model (SVM(all)) selected input features from all dose and non-dose factors. For comparison, the other model (SVM(dose)) selected input features only from lung dose-volume factors. Model predictive ability was evaluated using ten-fold cross-validation and receiver operating characteristics (ROC) analysis. For the model SVM(all), the area under the cross-validated ROC curve was 0.76 (sensitivity/specificity = 74%/75%). Compared to the corresponding SVM(dose) area of 0.71 (sensitivity/specificity = 68%/68%), the predictive ability of SVM(all) was improved, indicating that non-dose features are important contributors to separating patients with and without pneumonitis. Among the input features selected by model SVM(all), the two with highest importance for predicting lung pneumonitis were: (a) generalized equivalent uniform doses close to the mean lung dose, and (b) chemotherapy prior to radiotherapy. The model SVM(all) is publicly available via internet access.

Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer

We sought to identify the bladder dose-volume factors associated with an increased risk of late urinary toxicity among prostate cancer patients treated with radiotherapy. This retrospective analysis included data from 128 prostate cancer patients treated on protocol with 2 Gy/fraction to 46 Gy followed by a boost to 78 Gy. The endpoint for this analysis was Grade 1 or greater late genitourinary (GU) toxicity occurring within two years of treatment. The Lyman-Kutcher-Burman, mean dose, threshold dose, and hottest volume models were fitted to the toxicity data using the maximum likelihood method. Model fits based on dose-volume histograms tended to fit the toxicity data better than models based on dose-wall histograms. The hottest volume (hotspot) model was found to be the best-fitting model investigated. The best fit was for the hottest 2.9% of bladder (95% CI, 1.1-6.8%). This model has an area under the receiver operating characteristic curve of 0.74. The hotspot model separated the patients into clinically meaningful subgroups with approximately 25% of the patients who received <78 Gy to the hottest 2.9% of bladder had GU toxicity at eight years compared with approximately 50% when the dose was > or =78 Gy (p = 0.002). This provides the first evidence supporting that bladder "hotspots" are related to GU toxicity within two years after external beam radiotherapy for prostate cancer. Confirming data are needed from other investigators. Particular attention should be given to hotspots higher than 78 Gy in bladder in radiation treatment planning.

Multivariable modeling of radiotherapy outcomes, including dose–volume and clinical factors

The probability of a specific radiotherapy outcome is typically a complex, unknown function of dosimetric and clinical factors. Current models are usually oversimplified. We describe alternative methods for building multivariable dose-response models. Representative data sets of esophagitis and xerostomia are used. We use a logistic regression framework to approximate the treatment-response function. Bootstrap replications are performed to explore variable selection stability. To guard against under/overfitting, we compare several analytical and data-driven methods for model-order estimation. Spearman's coefficient is used to evaluate performance robustness. Novel graphical displays of variable cross correlations and bootstrap selection are demonstrated. Bootstrap variable selection techniques improve model building by reducing sample size effects and unveiling variable cross correlations. Inference by resampling and Bayesian approaches produced generally consistent guidance for model order estimation. The optimal esophagitis model consisted of 5 dosimetric/clinical variables. Although the xerostomia model could be improved by combining clinical and dose-volume factors, the improvement would be small. Prediction of treatment response can be improved by mixing clinical and dose-volume factors. Graphical tools can mitigate the inherent complexity of multivariable modeling. Bootstrap-based variable selection analysis increases the reliability of reported models. Statistical inference methods combined with Spearman's coefficient provide an efficient approach to estimating optimal model order.