X. Wei

Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy.

PURPOSE In 2004, our institution began using four-dimensional computed tomography (4DCT) simulation and then intensity-modulated radiotherapy (IMRT) (4DCT/IMRT) instead of three-dimensional conformal radiotherapy (3DCRT) for the standard treatment of non-small-cell lung cancer (NSCLC). This retrospective study compares disease outcomes and toxicity in patients treated with concomitant chemotherapy and either 4DCT/IMRT or 3DCRT. METHODS AND MATERIALS A total of 496 NSCLC patients have been treated at M. D. Anderson Cancer Center between 1999 and 2006 with concomitant chemoradiotherapy. Among these, 318 were treated with CT/3DCRT and 91 with 4DCT/IMRT. Both groups received a median dose of 63 Gy. Disease end points were locoregional progression (LRP), distant metastasis (DM), and overall survival (OS). Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity end point was Grade >or=3 radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models. RESULTS Mean follow-up times in the 4DCT/IMRT and CT/3DCRT groups were 1.3 (range, 0.1-3.2) and 2.1 (range, 0.1-7.9) years, respectively. The hazard ratios for 4DCT/IMRT were <1 for all disease end points; the difference was significant only for OS. The toxicity rate was significantly lower in the IMRT/4DCT group than in the CT/3DCRT group. V20 was significantly higher in the 3DCRT group and was a significant factor in determining toxicity. Freedom from DM was nearly identical in both groups. CONCLUSIONS Treatment with 4DCT/IMRT was at least as good as that with 3DCRT in terms of the rates of freedom from LRP and DM. There was a significant reduction in toxicity and a significant improvement in OS.

Risk Factors for Pericardial Effusion in Inoperable Esophageal Cancer Patients Treated With Definitive Chemoradiation Therapy

PURPOSE To identify clinical and dosimetric factors influencing the risk of pericardial effusion (PCE) in patients with inoperable esophageal cancer treated with definitive concurrent chemotherapy and radiation therapy (RT). METHODS AND MATERIALS Data for 101 patients with inoperable esophageal cancer treated with concurrent chemotherapy and RT from 2000 to 2003 at our institution were analyzed. The PCE was confirmed from follow-up chest computed tomography scans and radiologic reports, with freedom from PCE computed from the end of RT. Log-rank tests were used to identify clinical and dosimetric factors influencing freedom from PCE. Dosimetric factors were calculated from the dose-volume histogram for the whole heart and pericardium. RESULTS The crude rate of PCE was 27.7% (28 of 101). Median time to onset of PCE was 5.3 months (range, 1.0-16.7 months) after RT. None of the clinical factors investigated was found to significantly influence the risk of PCE. In univariate analysis, a wide range of dose-volume histogram parameters of the pericardium and heart were associated with risk of PCE, including mean dose to the pericardium, volume of pericardium receiving a dose greater than 3 Gy (V3) to greater than 50 Gy (V50), and heart volume treated to greater than 32-38 Gy. Multivariate analysis selected V30 as the only parameter significantly associated with risk of PCE. CONCLUSIONS High-dose radiation to the pericardium may strongly increase the risk of PCE. Such a risk may be reduced by minimizing the dose-volume of the irradiated pericardium and heart.

Performance Evaluation of Automatic Anatomy Segmentation Algorithm on Repeat or Four-Dimensional Computed Tomography Images Using Deformable Image Registration Method

PURPOSE Auto-propagation of anatomic regions of interest from the planning computed tomography (CT) scan to the daily CT is an essential step in image-guided adaptive radiotherapy. The goal of this study was to quantitatively evaluate the performance of the algorithm in typical clinical applications. METHODS AND MATERIALS We had previously adopted an image intensity-based deformable registration algorithm to find the correspondence between two images. In the present study, the regions of interest delineated on the planning CT image were mapped onto daily CT or four-dimensional CT images using the same transformation. Postprocessing methods, such as boundary smoothing and modification, were used to enhance the robustness of the algorithm. Auto-propagated contours for 8 head-and-neck cancer patients with a total of 100 repeat CT scans, 1 prostate patient with 24 repeat CT scans, and 9 lung cancer patients with a total of 90 four-dimensional CT images were evaluated against physician-drawn contours and physician-modified deformed contours using the volume overlap index and mean absolute surface-to-surface distance. RESULTS The deformed contours were reasonably well matched with the daily anatomy on the repeat CT images. The volume overlap index and mean absolute surface-to-surface distance was 83% and 1.3 mm, respectively, compared with the independently drawn contours. Better agreement (>97% and <0.4 mm) was achieved if the physician was only asked to correct the deformed contours. The algorithm was also robust in the presence of random noise in the image. CONCLUSION The deformable algorithm might be an effective method to propagate the planning regions of interest to subsequent CT images of changed anatomy, although a final review by physicians is highly recommended.

Long-Term Clinical Outcome of Intensity-Modulated Radiotherapy for Inoperable Non-Small Cell Lung Cancer: The MD Anderson Experience

PURPOSE In 2007, we published our initial experience in treating inoperable non-small-cell lung cancer (NSCLC) with intensity-modulated radiation therapy (IMRT). The current report is an update of that experience with long-term follow-up. METHODS AND MATERIALS Patients in this retrospective review were 165 patients who began definitive radiotherapy, with or without chemotherapy, for newly diagnosed, pathologically confirmed NSCLC to a dose of ≥60 Gy from 2005 to 2006. Early and late toxicities assessed included treatment-related pneumonitis (TRP), pulmonary fibrosis, esophagitis, and esophageal stricture, scored mainly according to the Common Terminology Criteria for Adverse Events 3.0. Other variables monitored were radiation-associated dermatitis and changes in body weight and Karnofsky performance status. The Kaplan-Meier method was used to compute survival and freedom from radiation-related acute and late toxicities as a function of time. RESULTS Most patients (89%) had Stage III to IV disease. The median radiation dose was 66 Gy given in 33 fractions (range, 60-76 Gy, 1.8-2.3 Gy per fraction). Median overall survival time was 1.8 years; the 2-year and 3-year overall survival rates were 46% and 30%. Rates of Grade ≥3 maximum TRP (TRP(max)) were 11% at 6 months and 14% at 12 months. At 18 months, 86% of patients had developed Grade ≥1 maximum pulmonary fibrosis (pulmonary fibrosis(max)) and 7% Grade ≥2 pulmonary fibrosis(max). The median times to maximum esophagitis (esophagitis(max)) were 3 weeks (range, 1-13 weeks) for Grade 2 and 6 weeks (range, 3-13 weeks) for Grade 3. A higher percentage of patients who experienced Grade 3 esophagitis(max) later developed Grade 2 to 3 esophageal stricture. CONCLUSIONS In our experience, using IMRT to treat NSCLC leads to low rates of pulmonary and esophageal toxicity, and favorable clinical outcomes in terms of survival.

Dose-volume thresholds and smoking status for the risk of treatment-related pneumonitis in inoperable non-small cell lung cancer treated with definitive radiotherapy.

PURPOSE To identify clinical risk factors and dose-volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade > or = 3 TRP calculated from start of radiotherapy. Clinical factors and dose-volume parameters were analyzed for their association with risk of TRP. RESULTS Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan-Meier estimate of the incidence of grade > or = 3 TRP at 12 months was 22%. An analysis of dose-volume parameters identified a threshold dose-volume histogram (DVH) curve defined by V(20) < or = 25%, V(25) < or = 20%, V(35) < or = 15%, and V(50) < or = 10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade > or = 3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors. CONCLUSIONS The risk of TRP varied significantly, depending on radiation dose-volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP.

Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer.

Concurrent chemoradiation therapy, the standard of care for locally advanced nonsmall cell lung cancer (NSCLC), can cause life‐threatening pneumonitis and esophagitis. X‐ray (photon)‐based radiation therapy (RT) often cannot be given at tumoricidal doses without toxicity to proximal normal tissues. We hypothesized that proton beam therapy for most patients with NSCLC could permit higher tumor doses with less normal‐tissue toxicity than photon RT delivered as 3‐dimensional conformal RT (3D‐CRT) or intensity‐modulated RT (IMRT).

Obesity Increases the Risk of Chest Wall Pain From Thoracic Stereotactic Body Radiation Therapy

PURPOSE Stereotactic body radiation therapy (SBRT) is increasingly being used to treat thoracic tumors. We attempted here to identify dose-volume parameters that predict chest wall toxicity (pain and skin reactions) in patients receiving thoracic SBRT. PATIENTS AND METHODS We screened a database of patients treated with SBRT between August 2004 and August 2008 to find patients with pulmonary tumors within 2.5 cm of the chest wall. All patients received a total dose of 50 Gy in four daily 12.5-Gy fractions. Toxicity was scored according to the NCI-CTCAE V3.0. RESULTS Of 360 patients in the database, 265 (268 tumors) had tumors within <2.5 cm of the chest wall; 104 (39%) developed skin toxicity (any grade); 14 (5%) developed acute pain (any grade), and 45 (17%) developed chronic pain (Grade 1 in 22 cases [49%] and Grade 2 or 3 in 23 cases [51%]). Both skin toxicity and chest wall pain were associated with the V30, or volume of the chest wall receiving 30 Gy. Body mass index (BMI) was also strongly associated with the development of chest pain: patients with BMI≥29 had almost twice the risk of chronic pain (p=0.03). Among patients with BMI>29, diabetes mellitus was a significant contributing factor to the development of chest pain. CONCLUSION Safe use of SBRT with 50 Gy in four fractions for lesions close to the chest wall requires consideration of the chest wall volume receiving 30 Gy and the patients BMI and diabetic state.

Analysis of Radiation Pneumonitis Risk Using a Generalized Lyman Model

PURPOSE 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. METHODS AND MATERIALS 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. RESULTS 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. CONCLUSIONS 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.

Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States Over 10 Years: A Quality Research in Radiation Oncology Survey

PURPOSE To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006-2007 with those used in patients treated in 1998-1999. METHODS AND MATERIALS Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), consisting of records of 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and of 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006-2007 versus those for patients treated in 1998-1999. RESULTS Use of all recommended procedures for staging and treatment was more common in 2006-2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006-2007 (vs 42% in 1998-1999, P=.0001) and in 84% of patients with LS-SCLC in 2006-2007 (vs 58.3% in 1998-1999, P=.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs 45% in 1998-1999, P<.0001) and for 90% of LS-SCLC patients (vs 62.5% in 1998-1999, P<.0001). Use of the recommended radiation dose (59-74 Gy for NSCLC and 60-70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006-2007) versus 43% (1998-1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006-2007 versus 8% in 1998-1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006-2007 (vs 21% in 1998-1999). CONCLUSIONS Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also requires improvement.

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.

PURPOSE 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). METHODS AND MATERIALS 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. RESULTS The results presented here illustrate the impact of scoring system and level of toxicity on the relationship between MLD and RP risk. CONCLUSIONS These results facilitate quantitative comparisons between our data and studies of RP risk reported by others, and several examples of such comparisons are provided.