J. Belderbos

Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. METHODS Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. RESULTS Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. CONCLUSION Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

Comparing different NTCP models that predict the incidence of radiation pneumonitis

Purpose: To compare different normal tissue complication probability (NTCP) models to predict the incidence of radiation pneumonitis on the basis of the dose distribution in the lung. Methods and Materials: The data from 382 breast cancer, malignant lymphoma, and inoperable non-small-cell lung cancer patients from two centers were studied. Radiation pneumonitis was scored using the Southwestern Oncology Group criteria. Dose-volume histograms of the lungs were calculated from the dose distributions that were corrected for dose per fraction effects. The dose-volume histogram of each patient was reduced to a single parameter using different local dose-effect relationships. Examples of single parameters were the mean lung dose (MLD) and the volume of lung receiving more than a threshold dose (VDth). The parameters for the different NTCP models were fit to patient data using a maximum likelihood analysis. Results: The best fit resulted in a linear local dose-effect relationship, with the MLD as the resulting single parameter. The relationship between the MLD and NTCP could be described with a median toxic dose (TD50) of 30.8 Gy and a steepness parameter m of 0.37. The best fit for the relationship between the VDth and the NTCP was obtained with a Dth of 13 Gy. The MLD model was found to be significantly better than the VDth model (p 35%. For arbitrary dose distributions, an estimate of the uncertainty in the NTCP could be determined using the probability distribution of the parameter values of the Lyman-Kutcher-Burman model. Conclusion: The maximum likelihood method revealed that the underlying local dose-effect relation for radiation pneumonitis was linear (the MLD model), rather than a step function (the VDth model). Thus, for the studied patient population, the MLD was the most accurate predictor for the incidence of radiation pneumonitis.PURPOSE To compare different normal tissue complication probability (NTCP) models to predict the incidence of radiation pneumonitis on the basis of the dose distribution in the lung. METHODS AND MATERIALS The data from 382 breast cancer, malignant lymphoma, and inoperable non-small-cell lung cancer patients from two centers were studied. Radiation pneumonitis was scored using the Southwestern Oncology Group criteria. Dose-volume histograms of the lungs were calculated from the dose distributions that were corrected for dose per fraction effects. The dose-volume histogram of each patient was reduced to a single parameter using different local dose-effect relationships. Examples of single parameters were the mean lung dose (MLD) and the volume of lung receiving more than a threshold dose (V(Dth)). The parameters for the different NTCP models were fit to patient data using a maximum likelihood analysis. RESULTS The best fit resulted in a linear local dose-effect relationship, with the MLD as the resulting single parameter. The relationship between the MLD and NTCP could be described with a median toxic dose (TD(50)) of 30.8 Gy and a steepness parameter m of 0.37. The best fit for the relationship between the V(Dth) and the NTCP was obtained with a D(th) of 13 Gy. The MLD model was found to be significantly better than the V(Dth) model (p <0.03). However, for 85% of the studied patients, the difference in NTCP calculated with both models was <10%, because of the high correlation between the two parameters. For dose distributions outside the range of the studied dose-volume histograms, the difference in NTCP, using the two models could be >35%. For arbitrary dose distributions, an estimate of the uncertainty in the NTCP could be determined using the probability distribution of the parameter values of the Lyman-Kutcher-Burman model. CONCLUSION The maximum likelihood method revealed that the underlying local dose-effect relation for radiation pneumonitis was linear (the MLD model), rather than a step function (the V(Dth) model). Thus, for the studied patient population, the MLD was the most accurate predictor for the incidence of radiation pneumonitis.

Impact of Introducing Stereotactic Lung Radiotherapy for Elderly Patients With Stage I Non–Small-Cell Lung Cancer: A Population-Based Time-Trend Analysis

PURPOSE Stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) is associated with high local control rates. The impact of introducing SBRT in patients 75 years of age or older was studied using a population-based cancer registry. METHODS The Amsterdam Cancer Registry was assessed in three eras: 1999 to 2001 (period A, pre-SBRT); 2002 to 2004 (period B, some availability of SBRT), and 2005 to 2007 (period C, full access to SBRT). χ(2), Kaplan-Meier, and Cox regression were used to compare treatment patterns and overall survival (OS) in three treatment groups: surgery, radiotherapy (RT), or neither. RESULTS A total of 875 elderly patients were diagnosed with stage I NSCLC in the study period. Median follow-up was 54 months. Primary treatment was surgery in 299 patients (34%), RT in 299 patients (34%), and neither in 277 patients (32%). RT use increased between periods A and C (26% v 42%, P < .01), corresponding to a decrease in untreated patients. The percentage of RT patients undergoing SBRT in periods B and C was 23% and 55%, respectively. Median survival for all patients increased from 16 months in period A to 21 months in period C (log-rank P < .01; hazard ratio [HR] = 0.65; 95% CI, 0.54 to 0.80). The improvement in OS was confined to RT patients (HR = 0.70; 95% CI, 0.49 to 0.99), whereas no significant survival improvements were seen in the other groups. CONCLUSION SBRT introduction was associated with a 16% absolute increase in RT use, a decline in the proportion of untreated elderly patients, and an improvement in OS.

Portal imaging to assess set-up errors, tumor motion and tumor shrinkage during conformal radiotherapy of non-small cell lung cancer

Abstract Purpose : To investigate patient set-up, tumor movement and shrinkage during 3D conformal radiotherapy for non-small cell lung cancer. Materials and methods : In 97 patients, electronic portal images (EPIs) were acquired and corrected for set-up using an off-line correction protocol based on a shrinking action level. For 25 selected patients, the orthogonal EPIs (taken at random points in the breathing cycle) throughout the 6–7 week course of treatment were assessed to establish the tumor position in each image using both an overlay and a delineation technique. The range of movement in each direction was calculated. The position of the tumor in the digitally reconstructed radiograph (DRR) was compared to the average position of the lesion in the EPIs. In addition, tumor shrinkage was assessed. Results : The mean overall set-up errors after correction were 0, 0.6 and 0.2 mm in the x (left–right), y (cranial–caudal) and z (anterior–posterior) directions, respectively. After correction, the standard deviations (SDs) of systematic errors were 1.4, 1.5 and 1.3 mm and the SDs of random errors were 2.9, 3.1 and 2.0 mm in the x -, y - and z -directions, respectively. Without correction, 41% of patients had a set-up error of more than 5 mm vector length, but with the set-up correction protocol this percentage was reduced to 1%. The mean amplitude of tumor motion was 7.3 (SD 2.7), 12.5 (SD 7.3) and 9.4 mm (SD 5.2) in the x -, y - and z -directions, respectively. Tumor motion was greatest in the y -direction and in particular for lower lobe tumors. In 40% of the patients, the projected area of the tumor regressed by more than 20% during treatment in at least one projection. In 16 patients it was possible to define the position of the center of the tumor in the DRR. There was a mean difference of 6 mm vector length between the tumor position in the DRR and the average position in the portal images. Conclusions : The application of the correction protocol resulted in a significant improvement in the set-up accuracy. There was wide variation in the observed tumor motion with more movement of lower lobe lesions. Tumor shrinkage was observed. The position of the tumor on the planning CT scan did not always coincide with the average position as measured during treatment.

Frameless Stereotactic Body Radiotherapy for Lung Cancer Using Four-Dimensional Cone Beam CT Guidance

PURPOSE To quantify the localization accuracy and intrafraction stability of lung cancer patients treated with frameless, four-dimensional (4D) cone beam computed tomography (CBCT)-guided stereotactic body radiotherapy (SBRT) and to calculate and validate planning target volume (PTV) margins to account for the residual geometric uncertainties. MATERIALS AND METHODS Sixty-five patients with small peripheral lung tumors were treated with SBRT without a body frame to 54 Gy in three fractions. For each fraction, three 4D-CBCT scans were acquired: before treatment to measure and correct the time-weighted mean tumor position, after correction to validate the correction applied, and after treatment to estimate the intrafraction stability. Patient-specific PTV margins were computed and subsequently validated using Monte Carlo error simulations. RESULTS Systematic tumor localization inaccuracies (1 SD) were 0.8, 0.8, and 0.9 mm for the left-right, craniocaudal, and anteroposterior direction, respectively. Random localization inaccuracies were 1.1, 1.1, and 1.4 mm. Baseline variations were 1.8, 2.9, and 3.0 mm (systematic) and 1.1, 1.5, and 2.0 mm (random), indicating the importance of image guidance. Intrafraction stability of the target was 1.2, 1.2, and 1.8 mm (systematic) and 1.3, 1.5, and 1.8 mm (random). Monte Carlo error simulations showed that patient-specific PTV margins (5.8-10.5 mm) were adequate for 94% of the evaluated cases (2-28 mm peak-to-peak breathing amplitude). CONCLUSIONS Frameless SBRT can be safely administered using 4D-CBCT guidance. Even with considerable breathing motion, the PTV margins can safely be kept small, allowing patients with larger tumors to benefit from the advantages of SBRT. In case bony anatomy would be used as a surrogate for tumor position, considerably larger PTV margins would be required.

COMPARISON OF DIFFERENT STRATEGIES TO USE FOUR-DIMENSIONAL COMPUTED TOMOGRAPHY IN TREATMENT PLANNING FOR LUNG CANCER PATIENTS

PURPOSE To discuss planning target volumes (PTVs) based on internal target volume (PTVITV), exhale-gated radiotherapy (PTVGating), and a new proposed midposition (PTVMidP; time-weighted mean tumor position) and compare them with the conventional free-breathing CT scan PTV (PTVConv). METHODS AND MATERIALS Respiratory motion induces systematic and random geometric uncertainties. Their contribution to the clinical target volume (CTV)-to-PTV margins differs for each PTV approach. The uncertainty margins were calculated using a dose-probability-based margin recipe (based on patient statistics). Tumor motion in four-dimensional CT scans was determined using a local rigid registration of the tumor. Geometric uncertainties for interfractional setup errors and tumor baseline variation were included. For PTVGating, the residual motion within a 30% gating (time) window was determined. The concepts were evaluated in terms of required CTV-to-PTV margin and PTV volume for 45 patients. RESULTS Over the patient group, the PTVITV was on average larger (+6%) and the PTVGating and PTVMidP smaller (-10%) than the PTVConv using an off-line (bony anatomy) setup correction protocol. With an on-line (soft tissue) protocol the differences in PTV compared with PTVConv were +33%, -4%, and 0, respectively. CONCLUSIONS The internal target volume method resulted in a significantly larger PTV than conventional CT scanning. The exhale-gated and mid-position approaches were comparable in terms of PTV. However, mid-position (or mid-ventilation) is easier to use in the clinic because it only affects the planning part of treatment and not the delivery.

Neurobehavioral Status and Health-Related Quality of Life in Newly Diagnosed High-Grade Glioma Patients

PURPOSE To evaluate the health-related quality of life (HRQOL) and cognitive functioning of high-grade glioma patients in the postneurosurgical period. PATIENTS AND METHODS The HRQOL, as assessed by the Short-Form Health Survey-36, tumor-specific symptoms, and objective and subjective neuropsychologic functioning, of 68 newly diagnosed glioma patients were compared with that of 50 patients with non-small-cell lung cancer (NSCLC) and to age- and sex-matched healthy controls. The association between tumor lateralization, extent of resection, and use of medication, and the HRQOL outcomes was also investigated. RESULTS The HRQOL of the two patient groups was similar but significantly lower than that of the healthy controls. Glioma patients reported significantly more neurologic symptoms and poorer objective and subjective neuropsychologic functioning than the NSCLC patients. Using healthy controls as the reference group, cognitive impairment assessed at the individual patient level was observed in all glioma patients and 52% of the NSCLC patients. Poor performance on timed tasks in the glioma group could be attributed, in large part, to visual and motor deficits. Tumor lateralization was found to affect neuropsychologic functioning in a predictable manner. The extent of resection was not related significantly to neuropsychologic functioning. Corticosteroid use was associated with better recognition memory, whereas antiepileptic drug use was correlated negatively with working memory capacity. CONCLUSION The general HRQOL of glioma patients is similar to that of patients with NSCLC. However, they suffer from a number of condition-specific neurologic and neuropsychologic problems that have a significant impact on their daily lives in the postsurgical period, before treatment with radiotherapy.

The PET-boost randomised phase II dose-escalation trial in non-small cell lung cancer

PURPOSE The local site of relapse in non-small cell lung cancer (NSCLC) is primarily located in the high FDG uptake region of the primary tumour prior to treatment. A phase II PET-boost trial (NCT01024829) randomises patients between dose-escalation of the entire primary tumour (arm A) or to the high FDG uptake region inside the primary tumour (>50% SUV(max)) (arm B), whilst giving 66 Gy in 24 fractions to involved lymph nodes. We analysed the planning results of the first 20 patients for which both arms A and B were planned. METHODS Boost dose levels were escalated up to predefined normal tissue constraints with an equal mean lung dose in both arms. This also forces an equal mean PTV dose in both arms, hence testing pure dose-redistribution. Actual delivered treatment plans from the ongoing clinical trial were analysed. Patients were randomised between arms A and B if dose-escalation to the primary tumour in arm A of at least 72 Gy in 24 fractions could be safely planned. RESULTS 15/20 patients could be escalated to at least 72 Gy. Average prescribed fraction dose was 3.27±0.31 Gy [3.01-4.28 Gy] and 3.63±0.54 Gy [3.20-5.40 Gy] for arms A and B, respectively. Average mean total dose inside the PTV of the primary tumour was comparable: 77.3±7.9 Gy vs. 77.5±10.1 Gy. For the boost region dose levels of on average 86.9±14.9 Gy were reached. No significant dose differences between both arms were observed for the organs at risk. Most frequent observed dose-limiting constraints were the mediastinal structures (13/15 and 14/15 for arms A and B, respectively), and the brachial plexus (3/15 for both arms). CONCLUSION Dose-escalation using an integrated boost could be achieved to the primary tumour or high FDG uptake regions whilst keeping the pre-defined dose constraints.

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PURPOSE To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. PATIENTS AND METHODS The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status <or=2, weight loss <10% and no chemotherapy within 6 weeks prior to the start of the radiotherapy treatment. No elective nodal irradiation was given. Patients were treated 5 days a week with 2.25 Gy per fraction and a 6 weeks overall treatment time; two fractions a day were given if more than 30 fractions were prescribed. Five risk groups were defined according to the relative mean lung dose (rMLD). Within each group the dose was escalated with three fractions per step (6.75 Gy). The next dose level opened after a toxicity-free follow-up of 6 months in three patients. The maximum tolerable dose has been reached if two out of six patients experience a dose-limiting toxicity (pneumonitis >or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). RESULTS Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. CONCLUSION Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

Adaptive Radiotherapy for Lung Cancer

Lung cancer radiation therapy (RT) is associated with complex geometrical uncertainties, such as respiratory motion, differential baseline shifts between primary tumor and involved lymph nodes, and anatomical changes due to treatment response. Generous safety margins required to account for these uncertainties limit the potential of dose escalation to improve treatment outcome. Four dimensional inverse planning incorporating pretreatment patient-specific respiratory motion information into the treatment plan already improves treatment plan quality. More importantly, repetitive imaging during treatment quantifies patient-specific intrafraction, interfraction, and progressive geometrical variations. These patient-specific parameters subsequently can drive adaptive plan modification correcting for systematic errors while incorporating random errors. Adaptive RT therefore has the potential to considerably improve the accuracy of RT, reducing the exposure of organs at risk, facilitating safe dose escalation, and improving local control as well as overall survival.